Methods and medicaments for administration of ibuprofen

ABSTRACT

A method for administration of ibuprofen to a subject in need of ibuprofen treatment is provided, in which an oral dosage form comprising a therapeutically effective amount of ibuprofen and a therapeutically effective amount of famotidine is administered three times per day.

1.0 CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/489,705; a continuation-in-part of U.S. patent applicationSer. No. 11/489,272; a continuation-in-part of U.S. patent applicationSer. No. 11/489,269 and a continuation-in-part of U.S. patentapplication Ser. No. 11/489,275 (all filed Jul. 18, 2006), and claimsbenefit under 35 USC §119(e) to U.S. provisional application No.60/897,371 (filed Jan. 24, 2007). The entire contents of each of theseapplications is herein incorporated by reference for all purposes.

2.0 FIELD OF THE INVENTION

The invention relates to pharmaceutical compositions containingibuprofen and famotidine, and finds application in the field ofmedicine.

3.0 BACKGROUND OF THE INVENTION

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), has been usedin humans for nearly forty years. While generally regarded as safe,ibuprofen and other NSAIDs can cause gastritis, dyspepsia, and gastricand duodenal ulceration. Gastric and duodenal ulceration is aconsequence of impaired mucosal integrity resulting fromibuprofen-mediated inhibition of prostaglandin synthesis. Thisside-effect is a particular problem for individuals who take ibuprofenfor extended periods of time, such as patients suffering from rheumatoidarthritis and osteoarthritis.

The risk of developing gastric or duodenal ulceration can be reduced bycotherapy with the drug famotidine. Famotidine blocks the action of thehistamine type 2 (H2) receptor, leading to a reduction of acid secretionin the stomach. Reducing stomach acid with famotidine during treatmentwith certain nonsteroidal anti-inflammatory drugs is reported todecrease incidence of gastrointestinal ulcers (see Taha et al., 1996,“Famotidine for the prevention of gastric and duodenal ulcers caused bynonsteroidal anti-inflammatory drugs” N Engl J Med 334:1435-9, andRostom et al., 2002, “Prevention of NSAID-induced gastrointestinalulcers” Cochrane Database Syst Rev 4:CD002296).

Famotidine is used for treatment of heartburn, ulcers, and esophagitisat daily doses from 10 mg to 80 mg. Approved schedules of famotidineadministration include 10 or 20 mg QD or BID (for treatment ofheartburn), 20 mg or 40 mg QD (for healing ulcers, such as 40 mg HS for4-8 weeks for healing duodenal ulcers), 20 mg HS (maintenance dosefollowing healing of ulcer), 20 mg BID for 6 weeks (for treatment ofgastroesophageal reflux disease), and 20 or 40 mg BID (for treatment ofesophageal erosion). For treatment of Zollinger-Ellison Syndrome, adisease characterized by hypersecretion of gastric acid, doses of up to800 mg/day have been used.

Although NSAID plus famotidine cotherapy reduces risk of developinggastric or duodenal ulceration, present therapies are not widely used.More effective methods of treatment and pharmaceutical compositions areneeded. The present invention meets this and other needs.

4.0 BRIEF SUMMARY OF THE INVENTION

In one aspect the invention provides a method for reducing gastric acidwhile treating a patient with an ibuprofen-responsive condition. Themethod involves administering a first dose of an oral dosage formcontaining from 775 mg to 825 mg ibuprofen and from 25 mg to 28 mgfamotidine, where the ibuprofen and famotidine are present in a weightratio in the range 29:1 to 31:1, and where the ibuprofen and thefamotidine are formulated for immediate release; administering a seconddose of the oral dosage form; and administering a third dose of the oraldosage form, where the first dose, the second dose, and the third doseare administered within a 24 hour dosing cycle. In one embodiment, theibuprofen and the famotidine are admixed in the oral dosage form. In oneembodiment, the ibuprofen and the famotidine are in separatecompartments in the oral dosage form.

The ibuprofen and the famotidine may be formulated to release at least60% of the ibuprofen and the famotidine within about 20 minutes underneutral pH conditions.

In one aspect the invention provides an oral dosage form comprising from775 mg to 825 mg ibuprofen and from 25 mg to 28 mg famotidine, theibuprofen and famotidine being present in a weight ratio in the range29:1 to 31:1, where the ibuprofen and the famotidine are formulated forimmediate release. In one embodiment the oral dosage form comprises afirst portion containing ibuprofen and a second portion containingfamotidine, where the famotidine is in the form of barrier-coatedparticles distributed in the ibuprofen portion.

In one aspect the invention provides a method of reducing the likelihoodthat a patient receiving combined ibuprofen-famotidine therapy willexperience a 24-hour median pH less than 2.5, by administering a oralunit dosage form to the patient on a TID (three-times-per-day) schedule.

In one aspect the invention provides a method for reducingpatient-to-patient variability with respect to gastric pH in apopulation of patients in need of an ibuprofen-famotidine combinationtherapy by administering to patients in the population an oral unitdosage form containing ibuprofen and famotidine, where the ibuprofen andfamotidine are in a weight ratio in the range of 29:1 to 31:1, and theoral unit dose form is administered three-times-per-day (TID). In oneembodiment the oral unit dosage form contains about 800 mg ibuprofen andabout 26.67 mg famotidine or about 400 mg ibuprofen and about 13.33 mgfamotidine.

In one aspect the invention provides an improved method for treating apopulation of patients in need of an ibuprofen-famotidine combinationtherapy and reducing inter-patient variability with respect to gastricpH in the population. The method involves administering to patients inthe population an oral unit dosage form containing ibuprofen andfamotidine, where the ibuprofen and famotidine are in a weight ratio inthe range of 29:1 to 31:1, and the oral unit dose form is administeredthree-times-per-day.

In one aspect, the invention provides a method for administration ofibuprofen to a subject in need of ibuprofen treatment. The methodinvolves administering an oral dosage form containing a therapeuticallyeffective amount of ibuprofen and a therapeutically effective amount offamotidine, where the oral dosage form is administered three times perday (TID). In one embodiment, the ibuprofen and the famotidine are inseparate compartments of the oral dosage form. In one embodiment, theibuprofen and the famotidine are in admixture in the oral dosage form.In one embodiment, the famotidine and ibuprofen are released from thedosage form rapidly, e.g., under in vitro assay conditions.

In one embodiment, ibuprofen and famotidine are administered in dailydoses of about 2400 mg and about 80 mg respectively. In some embodimentsof this method, the oral dosage form contains ibuprofen and famotidinein a ratio in the range of 29:1 to 32:1, such as the range of 30:1 to31:1. In one embodiment, the oral dosage form contains 750 mg to 850 mg(e.g. about 800 mg) ibuprofen and 24 mg to 28 mg (e.g., about 26.6 mgfamotidine). In one embodiment, the oral dosage form contains 775 mg to825 mg (e.g. about 800 mg) ibuprofen and 24 mg to 28 mg (e.g., about26.6 mg famotidine). In another embodiment, the oral dosage formcontains 375 mg to 425 mg (e.g., about 400 mg) ibuprofen and 12 mg to 14mg (e.g., about 13 mg) famotidine.

In one embodiment, the TID administration of the dosage form providesbetter gastric protection for the subject over a 24-hour period than TIDadministration of the same daily quantity of ibuprofen and two times aday (BID) administration of the same daily quantity of famotidine. Inone embodiment, the daily quantity of ibuprofen is about 2400 mg and thedaily quantity of famotidine is about 80 mg. Thus, in certain aspects,the invention provides a method in which TID administration of a dosageform containing about 800 mg ibuprofen and about 26.6 mg famotidineprovides better gastric protection over a 24-hour period than TIDadministration of the 800 mg ibuprofen and BID administration of 40 mgfamotidine. Equivalently, TID administration of two oral dosage formscontaining about 400 mg ibuprofen and about 13 mg (e.g., about 13.3 mg)famotidine provides better gastric protection over a 24-hour period thanTID administration 800 mg ibuprofen in a single or split dose and BIDadministration of 40 mg famotidine in a single or split dose.

Ibuprofen, in the form of a unit dose form of the invention, may beadministered to a subject is in need of ibuprofen treatment. In variousembodiments, the subject is in need of ibuprofen treatment for a chroniccondition (such as rheumatoid arthritis, osteoarthritis or chronic pain)or a condition such as acute or moderate pain, dysmenorrhea or acuteinflammation.

In a different aspect the invention provides a solid oral dosage formhaving a first portion containing a therapeutically effective amount ofibuprofen and a second portion containing a therapeutically effectiveamount of famotidine, where the first portion completely surrounds thesecond portion or the second portion completely surrounds the firstportion; and having a barrier layer disposed between the first andsecond portions, where the ibuprofen and famotidine are released intosolution rapidly. In one embodiment an ibuprofen-containing core portionis surrounded by a famotidine-containing layer and a barrier layer isinterposed between the core portion and famotidine-containing layer.

In another aspect, a solid oral dosage form is provided which comprisesparticles of famotidine coated with a barrier layer and situated in amatrix containing ibuprofen or compressed into a tablet with ibuprofenand excipients. In one aspect, the ibuprofen is ibuprofen DC-85 fromBASF.

In one embodiment, the oral dosage form contains about 800 mg ibuprofenand about 26.6 mg (e.g., 26.67 mg) famotidine or about 400 mg ibuprofenand about 13 mg (e.g., 13.3 mg) famotidine. In some embodiments, theoral dosage form contains ibuprofen and famotidine in a ratio in therange of 29:1 to 32:1. In some embodiments, the oral dosage formcontains ibuprofen and famotidine in a ratio in the range of 29:1 to31:1.

In a specific embodiment, first portion comprises ibuprofen, 20-30%(w/w) lactose monohydrate; 0.1 to 2% colloidal silicon dioxide; 3-7%crosscarmellose sodium; 1-3% hydroxy propyl methyl cellulose; 2-6%silicified microcrystalline cellulose (Prosolv SMCC 90) and 0.1-2%magnesium stearate.

In one embodiment, at least 75% of the famotidine and at least 75% ofthe ibuprofen in the dosage form are released within 15 minutes whenmeasured in a Type II dissolution apparatus (paddles) according to U.S.Pharmacopoeia XXIX at 37° C. in 50 mM potassium phosphate buffer, pH 7.2at 50 rotations per minute.

In an aspect of the invention a method is provided for treating apatient in need of ibuprofen treatment, where the patient is at elevatedrisk for developing an NSAID-induced ulcer. The method involvesadministering an oral dosage form comprising a therapeutically effectiveamount of ibuprofen and a therapeutically effective amount offamotidine, where the oral dosage form is administered three times perday (TID), where the ibuprofen and the famotidine are optionally inseparate compartments of the oral dosage form, and where the famotidineand ibuprofen are released from the dosage form rapidly when agitated in50 mM potassium phosphate buffer, pH 7.2 at 37° C. In one embodiment ofthis method the oral dosage form may contain ibuprofen and famotidine ina ratio in the range of 30:1 to 31:1.

In an aspect of the invention a method is provided for reducing symptomsof dyspepsia in a subject in need of NSAID treatment who has experiencedsymptoms of dyspepsia associated with NSAID administration, comprisingadministering to the subject an effective amount of a NSAID incombination with an effective amount of famotidine, where the famotidineis administered three times per day. In one embodiment of this methodthe NSAID is ibuprofen. In one embodiment of this method from 25 mg to27 mg famotidine is administered three times per day. In one embodimentof this method the famotidine and NSAID are administered as a singleoral unit dose form.

In an aspect of the invention a method is provided for treating a personin need of famotidine treatment by administering from 25 mg to 27 mgfamotidine three times per day. In a related aspect, the inventionprovides a solid oral dosage form comprising famotidine or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients, where the dosage form comprisesabout 13 mg (e.g., 13.3 mg) or about 26.6 mg famotidine. In oneembodiment famotidine is the only pharmaceutically active ingredient inthe dosage form.

In an aspect of the invention a method is provided for administration ofibuprofen to a subject by providing an oral dosage form comprising 750mg to 850 mg ibuprofen and 24 mg to 28 mg famotidine, where theibuprofen and famotidine are present in a ratio in the range of 29:1 to32:1; or in the range of 29:1 to 31:1, administering a first dose of theoral dosage form; administering a second dose of the oral dosage form;and administering a third dose of the oral dosage form, where the firstdose, the second dose, and the third dose are administered within a 24hour dosing cycle.

5.0 BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the predicted effect on intragastric pH of administrationof 26.6 mg famotidine TID. FIG. 1A (upper panel) shows the predictedintragastric pH during TID dosing of famotidine (80 mg/day). FIG. 1B(lower panel) shows the predicted plasma famotidine concentration duringTID dosing of famotidine (80 mg/day).

FIG. 2 shows the predicted effect on intragastric pH of administrationof 40 mg famotidine BID. FIG. 2A (upper panel) shows the predictedintragastric pH during BID dosing of famotidine (80 mg/day). FIG. 2B(lower panel) shows the predicted plasma famotidine concentration duringBID dosing of famotidine (80 mg/day).

6.0-18.10 DETAILED DESCRIPTION 6.0 Definitions

“Famotidine” is3-[2-(diaminomethyleneamino)thiazol-4-ylmethylthio]-N-sulfamoylpropionamidine, including the polymorphic forms designated Form A andForm B (see, e.g. U.S. Pat. Nos. 5,128,477 and 5,120,850) and theirmixtures, as well as pharmaceutically acceptable salts thereof.Famotidine can be prepared using art-known methods, such as the methoddescribed in U.S. Pat. No. 4,283,408. Famotidine's properties have beendescribed in the medical literature (see, e.g., Echizen et al., 1991,Clin Pharmacokinet. 21:178-94).

“Ibuprofen” is 2-(p-isobutylphenyl) propionic acid (C₁₃H₁₈O₂), includingvarious crystal forms and pharmaceutically acceptable salts. Twoenantiomers of ibuprofen exist. As used herein in the context of solidformulations of the invention, “ibuprofen” refers to a racemic mixtureor either enantiomer (including, for example, mixtures enriched in theS-enantiomer, and compositions substantially free of the R-enantiomer).Ibuprofen is available commercially and, for example, ibuprofenpreparations with mean particle sizes of 25, 38, 50, or 90 microns canbe obtained from BASF Aktiengesellschaft (Ludwigshafen, Germany). Oneuseful ibuprofen product is directly compressible formulation describedin WO 2007/042445 (incorporated herein by reference), a version of whichis available from BASF under the trade name Ibuprofen DC 85™.Ibuprofen's properties have been described in the medical literature(see, e.g., Davies, 1998, “Clinical pharmacokinetics of ibuprofen. Thefirst 30 years” Clin Pharmacokinet 34:101-54).

An “API” is an active pharmaceutical ingredient. As used herein, “API”refers to ibuprofen and/or famotidine.

A “therapeutically effective amount” of ibuprofen is an amount ofibuprofen or its pharmaceutically acceptable salt which eliminates,alleviates, or provides relief of the symptoms for which it isadministered.

A “therapeutically effective amount” of famotidine is an amount offamotidine or its pharmaceutically acceptable salt which suppressesgastric acid secretion.

The terms “solid oral dosage form,” “oral dosage form,” “unit doseform,” “dosage form for oral administration,” and the like are usedinterchangably, and refer to a pharmaceutical composition in the form ofa tablet, capsule, caplet, gelcap, geltab, pill and the like.

An “excipient,” as used herein, is any component of an oral dosage formthat is not an API. Excipients include binders, lubricants, diluents,disintegrants, coatings, barrier layer components, glidants, and othercomponents. Excipients are known in the art (see HANDBOOK OFPHARMACEUTICAL EXCIPIENTS, FIFTH EDITION, 2005, edited by Rowe et al.,McGraw Hill). Some excipients serve multiple functions or are so-calledhigh functionality excipients. For example, talc may act as a lubricant,and an anti-adherent, and a glidant. See Pifferi et al., 2005, “Qualityand functionality of excipients” Farmaco. 54:1-14; and Zeleznik andRenak, Business Briefing: Pharmagenerics 2004.

A “binder” is an excipient that imparts cohesive qualities to componentsof a pharmaceutical composition. Commonly used binders include, forexample, starch; sugars, such as, sucrose, glucose, dextrose, andlactose; cellulose derivatives such as powdered cellulose,microcrystalline cellulose, silicified microcrystalline cellulose(SMCC), hydroxypropylcellulose, low-substituted hydroxypropylcellulose,hypromellose (hydroxypropylmethylcellulose); and mixtures of these andsimilar ingredients.

A “lubricant” is an excipient added to reduce sticking by a solidformulation to the equipment used for production of a unit does form,such as, for example, the punches of a tablet press. Examples oflubricants include magnesium stearate and calcium stearate. Otherlubricants include, but are not limited to, aluminum-stearate, talc,sodium benzoate, glyceryl mono fatty acid (e.g. glyceryl monostearatefrom Danisco, UK), glyceryl dibehenate (e.g. CompritolATO888™ GattefosseFrance), glyceryl palmito-stearic ester (e.g. Precirol™, GattefosseFrance), polyoxyethylene glycol (PEG, BASF) such as PEG 4000-8000,hydrogenated cotton seed oil or castor seed oil (Cutina H R, Henkel) andothers.

A “diluent” is an excipient added to a pharmaceutical composition toincrease bulk weight of the material to be formulated, e.g. tabletted,in order to achieve the desired weight.

The term “disintegrant” refers to excipients included in apharmaceutical composition in order to ensure that the composition hasan acceptable disintegration rate in an environment of use. Examples ofdisintegrants include starch derivatives (e.g., sodium carboxymethylstarch and pregelatinized corn starch such as starch 1500 from Colorcon)and salts of carboxymethylcellulose (e.g., sodiumcarboxymethylcellulose), crospovidone (cross-linked PVPpolyvinylpyrrolidinone (PVP), e.g., Polyplasdone™ from ISP or Kollidon™from BASF).

The term “glidant” is used to refer to excipients included in apharmaceutical composition to keep the component powder flowing as atablet is being made, preventing formation of lumps. Nonlimitingexamples of glidants are colloidal silicon dioxides such as CAB-O-SIL™(Cabot Corp.), SYLOID™, (W.R. Grace & Co.), AEROSIL™ (Degussa), talc,and corn starch.

The term “nonionic surfactant” refers to, for example and notlimitation, sucrose esters; partial fatty acid esters ofpolyhydroxyethylenesorbitan, such as polyethylene glycol(20) sorbitanmonolaurate, monopalmitate, monostearate and monooleate; polyethyleneglycol(20) sorbitan tristearate and trioleate); polyethylene glycol(4)sorbitan monolaurate and monostearate; polyethylene glycol(5) sorbitanmonooleate; polyhydroxyethylene fatty alcohol ethers such aspolyoxyethylene cetyl stearyl ether or corresponding lauryl ethers;polyhydroxyethylene fatty acid esters; ethylene oxide/propylene oxideblock copolymers; sugar ethers and sugar esters; phospholipids and theirderivatives; and ethoxylated triglycerides such as the derivatives ofcastor oil. Examples include Cremophor™ RH 40; Cremophor™ RH 60, Tween™80.

The terms “over-coating,” “over-coating layer,” or “over-coat” refer toan outer most coating or coatings of a unit dose form such as a tabletor caplet, which may be added to improve appearance, taste,swallowability, or other characteristics of the tablet or caplet. Theover-coating layer does not contain an API. Suitable over-coatings aresoluble in, or rapidly disintegrate in water, and, for purposes of thisinvention, are not enteric coatings. An exemplary over-coating materialis Opadry II available from Colorcon, Inc., Westpoint Pa.

“QD”, “BID”, “TID”, “QID”, and “HS” have their usual meanings of,respectively, administration of medicine once per day, twice per day,three times per day, four times per day or at bedtime. Administrationthree times per day means that at least 6 hours, preferably at least 7hours, and more preferably about 8 hours elapse between administrations.Administration three times per day can mean administration about every 8hours (e.g., 7 a.m., 3 p.m. and 11 p.m.). In some cases in whichquantitative measurements are made, “TID administration” can meanadministration every 8±0.25 hours.

As used herein, the term “daily quantity” refers to the quantity of anAPI (ibuprofen or famotidine) administered over a 24-hour period under aspecific dosing regimen.

The term “barrier layer” refers a layer in the unit dosage form that isinterposed between the ibuprofen-containing compartment (e.g., anibuprofen core or coated ibuprofen particles) and thefamotidine-containing compartment (e.g., famotidine-containing coatingor coated famotidine particles). Generally, the barrier layer does notcontain an API. A barrier layer of the invention may be a water-soluble,pH independent film that promotes immediate disintegration for rapidrelease of the coated drug (i.e., ibuprofen and/or famotidine). Usuallya readily soluble film is used. Materials that can be used for readilysoluble films are well known in the art and include cellulosederivatives such as hydroxypropylmethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetatephthalate, and ethyl cellulose; methacrylic polymers,amino-alkylmethacrylate copolymers (e.g. EudragitTME), polyvinyl acetatephthalate and polyvinyl alcohol (PVA). A plasticizer (e.g., triacetin,diethyl phthalate, tributyl sebacate or polyethylene glycol) may also beincluded. The barrier layer may include an anti-adherent or glidant(e.g., talc, fumed silica or magnesium stearate) and colorants such astitanium dioxide, iron oxide based colorants or others. In oneembodiment the barrier layer comprises a non-toxic edible polymer,edible pigment particles, an edible polymer plasticizer, and asurfactant. Materials include, for example and not limitation, materialsdescribed in U.S. Pat. No. 4,543,370 (Colorcon), incorporated herein byreference. Exemplary barrier layers include OPADRY®, which is availablefrom Colorcon (West Point Pa. USA); OPADRY II® which is available fromColorcon (West Point Pa. USA) and comprises HPMC, titanium dioxide,plasticizer and other components; and polyvinyl alcohol-polyethyleneglycol copolymer marketed as Kollicoat® IR (BASF). Suitable barrierlayers, for illustration and not limitation, include Kollicoat® IR (apolyvinyl alcohol-polyethylene glycol graft copolymer) and Kollicoat IRWhite® both manufactured by BASF Aktiengesellschaft (Ludwigshafen,Germany). The thickness of the barrier layer can vary over a wide range,but is generally in the range 20 to 3,000 microns, such as on the orderof about 25 to 250 microns. Preferably the barrier layer retards therelease of API by less than 5 minutes, preferably less than 4 minutesand more preferably by less than 3 minutes.

A “subject in need of ibuprofen treatment” is an individual who receivestherapeutic benefit from administration of ibuprofen. Ibuprofen isindicated for treatment of mild to moderate pain, dysmenorrhea,inflammation, and arthritis. In one embodiment, the subject in need ofibuprofen treatment is under treatment for a chronic condition. Forexample and without limitation, a subject in need of ibuprofen treatmentmay be an individual with rheumatoid arthritis, an individual withosteoarthritis, an individual suffering from chronic pain (e.g., chroniclow back pain, chronic regional pain syndrome, chronic soft tissuepain), or an individual suffering from a chronic inflammatory condition.In general, a subject under treatment for a chronic condition requiresibuprofen treatment for an extended period, such as at least one month,at least four months, at least six months, or at least one year. Inanother embodiment, the subject in need of ibuprofen treatment is undertreatment for a condition that is not chronic, such as acute pain,dysmenorrhea or acute inflammation. Preferably the patient in need ofibuprofen treatment does not suffer from a condition characterized byhypersecretion of gastric acid (e.g., Zollinger-Ellison Syndrome).Preferably the patient does not suffer from Barrett's ulceration oractive severe oesophagitis. In certain embodiments the subject does nothave gastroesophageal reflux disease (GERD). In certain embodiments thesubject is not in need of treatment for an ulcer. In certain embodimentsthe subject does not suffer from dyspepsia. In certain embodiments thesubject is at elevated risk of developing an NSAID-induced ulcer. Insome embodiments the subject has a Body Mass Index in the normal range.

An “ibuprofen responsive condition” is a condition for which symptomsare reduced by administration of ibuprofen, such as mild to moderatepain, dysmenorrhea, inflammation, arthritis (e.g., rheumatoid arthritisand osteoarthritis), chronic pain, chronic inflammatory condition,chronic pain, acute pain and acute inflammation.

A “subject in need of famotidine treatment” is an individual whoreceives therapeutic benefit from administration of famotidine. In oneembodiment, the subject in need of famotidine treatment requirestreatment for non-ulcerative dyspepsia. In one embodiment, the subjectin need of famotidine treatment requires treatment for gastroesophagealreflux disease (GERD) or for esophagitis due to GERD or for ulcer(duodenal or gastric). In one embodiment, the subject does not takeibuprofen for treatment of a chronic condition. In one embodiment, thesubject is not under NSAID therapy (e.g., does not take ibuprofen and/ora different NSAID for treatment of a chronic condition). In oneembodiment, the subject in need of famotidine treatment requirestreatment for dyspepsia but does not require treatment for ulcer, GERDor its complications. As used herein, “subject in need of famotidinetreatment” specifically excludes any subject in need of treatment forhypersecretion of gastric acid (e.g., Zollinger-Ellison Syndrome). Incertain embodiment, the patient does not suffer from Barrett'sulceration or active severe oesophagitis. In certain embodiments a“subject in need of famotidine treatment” does not suffer fromgastroesophageal reflux disease (GERD) or esophagitis due to GERD. Incertain embodiments a “subject in need of famotidine treatment” does nothave an ulcer. In certain embodiments the subject does not suffer fromdyspepsia.

A “famotidine responsive condition” is a condition for which symptomsare reduced by administration of famotidine, such as dyspepsia, GERD,esophagitis due to GERD, or ulcer.

A subject is “at elevated risk for developing an NSAID-induced ulcer” ifthe subject in more susceptible than the average individual todevelopment of an ulcer when under treatment with an NSAID. A high oddsratio for risk of development of NSAID-associated ulcer complications isseen in individuals with a past complicated ulcer (odds ratio 13.5),individuals taking multiple NSAIDs or NSAIDs plus aspirin (odds ratio9.0); individuals taking high doses of NSAIDs (odds ratio 7.0),individuals under anticoagulant therapy, such as low dose aspirin (oddsration 6.4), individuals with a past uncomplicated ulcer (odds ratio6.1), and individuals older than 70 years (odds ratio 5.6) See, e.g.,Gabriel et al., 1991, Ann Intern Med. 115:787; Garcia Rodriguez et al.1994, Lancet 343:769; Silverstein et al. 1995, Ann Intern Med. 123:241;and Sorensen et al., 2000, Am J Gastroenterol. 95:2218. Subjects atincreased risk for developing an NSAID-induced ulcer may have one ormore of these risk factors. Subjects “at high risk for developing anNSAID-induced ulcer” are individuals older than 80 years of age andsubjects with a history of NSAID-associated serious gastrointestinalcomplications (e.g., perforation of ulcers, gastric outlet obstructiondue to ulcers, gastrointestinal bleeding).

“Admixture” refers to a pharmaceutical composition made by combining andmixing two or more drugs and one or more excipients in the samecompartment of a unit dosage form.

A “compartment” in the context of a unit dosage form is a physicalregion of a tablet or other dosage form. Two components of a unit dosageform are in “separate compartments” when they are physically separated(e.g., by a barrier layer).

As used herein in the context of a unit dosage form, the term “enteric”has its usual meaning and refers to a medicinal preparation that passesthrough the stomach intact and disintegrates in the intestine. An“enteric coating” remains insoluble at gastric pH, then allows forrelease of the active ingredient from a coated particle or coated dosageform at pH greater than about 5.0, e.g., greater than pH 5.5, 6.0, 6.5,or 7.0

As used herein, “dyspepsia” refers to upper abdominal pain or discomfortwith or without symptoms of early satiety, nausea, or vomiting with nodefinable organic cause, as diagnosed following the Rome II criteria(Talley et al., 1999, Gut 45 (Suppl. II):1137-42), or any subsequentmodification thereof. According to the Rome II criteria, a diagnosis offunctional dyspepsia requires: (1) persistent or recurrent abdominalpain or discomfort centered in the upper abdomen; (2) symptom durationof at least 12 weeks, which need not be consecutive, within thepreceding 12 months; (3) no evidence of organic disease (including atupper endoscopy) that is likely to explain symptoms; (4) no evidencethat dyspepsia is exclusively relieved by defecation or association withthe onset of a change in the stool frequency or stool form (i.e., notirritable bowel syndrome). In this context, “discomfort” is defined asan unpleasant sensation, and may include fullness, bloating, earlysatiety, and nausea. The definition includes, without limitation,ulcer-like, dysmotility-like, and non-specific dyspepsia. Symptoms ofdyspepsia include nausea, regurgitation, vomiting, heartburn, prolongedabdominal fullness or bloating after a meal, stomach discomfort or pain,and early fullness.

A unit dose form is in an “aqueous environment” when it is in awater-based solution in vivo (e.g., in the stomach) or in vitro. One invitro aqueous environment is 50 mM potassium phosphate buffer, pH 7.2.Another in vitro aqueous environment is 50 mM potassium phosphatebuffer, pH 4.5.

As used herein, a person with “normal body weight” has a body mass indexof 20-25 inclusive (calculated as weight (kg)/[height (m)]²).

As used herein, a “24-hour dosing cycle” or “24-hour dosing period”refers to a 24-hour period of time during which a subject isadministered drug(s) and may correspond to a calender day (e.g., 12:01a.m. to midnight) or may span two calender days (noon day 1 to noon day2).

All percentages are % w/w, unless specifically indicated otherwise.Unless otherwise indicated, “% weight” is percent weight of thespecified component compared to the total weight of the unit dosage(e.g., tablet). Optionally the % weight can be calculated as if thetotal weight of the unit dosage form is the weight of the ibuprofenportion, famotidine portion, and barrier layer, but not including theover-coating (e.g., added to mask taste, improve ease of swallowing, toimprove appearance, and the like). Optionally the % weight can becalculated based on the total weight of the unit dosage form, includingall coatings. “United States Pharmacopeia” and “USP” mean the UnitedStates Pharmacopeia and National Formulary 29th Revision (available from12601 Twinbrook Parkway, Rockville, Md. 20852-1790, USA). It will beappreciated that due to rounding or practical limits on quantitivemeasurements, reference to a quantity of API or excipient in a dosageform can include some variation, such as ±10%, preferably ±5%, and morepreferably ±1%. It will be appreciated, for example, that a totalquantity of 80 mg famotidine can be administered in three doses of 26.6mg famotidine per dose.

7.0 TID Administration of Ibuprofen-Famotidine Oral Dosage Form

In one aspect the present invention relates to administration of an oraldosage form comprising ibuprofen, famotidine, and one or morepharmaceutically acceptable excipients, to a patient in need ofibuprofen treatment. In part, the present invention is directed to amethod of reducing or preventing the occurrence of gastrointestinaltoxicity associated with the use of ibuprofen, such as gastrointestinalulceration and dyspepsia. In one embodiment, the invention is directedto a method for preventing toxicities associated with ibuprofen use inpatients who are specifically at risk for the development of suchtoxicities.

When administered to avoid or mitigate the ulcerogenic effects oflong-term NSAID therapy, famotidine is administered at 40 mg BID (seeTaha et al., 1996, supra). However, it has now been determined usingpharmacokinetic modeling (see Example 1) and in clinical trials (seeExample 2) that, surprisingly, TID administration of famotidine providesa protective effect superior to that achieved by BID dosing. Forexample, TID administration of famotidine results in intragastric pHhigher than 3.5 for a greater proportion of the dosing cycle thanconventional BID dosing.

Unexpectedly, treatment using the methods of the present inventionresult in reduced interpatient variability with respect to gastric pH ina population of patients receiving an ibuprofen-famotidine combinationtreatment. This reduction increases predictability of the treatment andreduces the likelihood that any particular patient will experiencedetrimental gastric pH in the course of ibuprofen-famotidine combinationtreatment.

In addition, a human clinical study described in Example 3, below, hasshown that the pharmocokinetic parameters for concurrent administrationof immediate release forms of ibuprofen and famotidine were notsignificantly different from pharmocokinetic parameters for separateadministration of the two APIs. When administered concurrently, bothibuprofen and famotidine retain immediate release characteristics ofrapid absorption and rapid attainment of the maximum plasmaconcentration (T_(max)).

These data indicate that a treatment paradigm in which ibuprofen andfamotidine are administered as a unit dose form on a TID (three timesper day) schedule will deliver ibuprofen that is bioequivalent to thatof conventional TID dosing of ibuprofen, while providing significant andsuperior protection from ibuprofen-related side effects such asincreased likelihood ulcer development and dyspepsia. Administration ofibuprofen-famotidine TID will provide superior protection, as measuredby gastric pH, compared to cotherapy with famotidine BID and ibuprofenTID.

Thus, in one aspect, the present invention provides a method foradministration of ibuprofen to a patient in need of ibuprofen treatmentby administering an oral dosage form comprising a therapeuticallyeffective amount of ibuprofen and a therapeutically effective amount offamotidine, where the oral dosage form is administered three times perday (TID). The invention also provides oral unit dosage forms adaptedfor use in this method.

8.0 Incompatibility of Ibuprofen and Famotidine

It has been discovered that, under “forced degradation” conditions,ibuprofen and famotidine in admixture are pharmaceutically incompatible.Forced degradation conditions refer to conditions of elevatedtemperature, or elevated temperature and humidity, intended toaccelerate the process of chemical degradation. Forced degradationconditions for a period of time are used to predict the effect ofstorage under more benign conditions (e.g., room temperature) for alonger period of time. The present invention overcomes thisincompatibility by formulating the ibuprofen and famotidine in separatecompartments of the dosage form.

Thus in one aspect, the present invention provides a method foradministration of ibuprofen to a patient in need of ibuprofen treatmentby administering an oral dosage form comprising a therapeuticallyeffective amount of ibuprofen and a therapeutically effective amount offamotidine, wherein the oral dosage form is administered three times perday (TID), and wherein the ibuprofen and the famotidine are in separatecompartments of the oral dosage form. The invention also provides oralunit dosage forms adapted for use in this method.

Surprisingly, however, in certain formulations ibuprofen and famotidineare stable in admixture at room temperature. Thus, alternatively, theinvention overcomes the incompatibility of ibuprofen and famotidine byselection of the formulation components (see, e.g., Example 4 andexemplary unit dose form VII, below).

9.0 Ibuprofen-Famotidine Oral Dosage Forms API Content, DissolutionProperties and Protective Properties

Exemplary formulations that may be used in the practice of the inventionare described below.

9.1 API Content

The dosage forms of the invention comprise ibuprofen and famotidine inamounts sufficient to provide therapeutic efficacy when administeredthree times per day. At each administration time, a single unit dosageform (e.g., tablet) may be administered, or the appropriate amount ofdrug can be administered as a split dose (e.g., the same amount of drugadministered as two tablets taken together). For example, TIDadministration of 800 mg ibuprofen and 26.6 mg famotidine can be in theform of a single unit dosage form containing 800 mg ibuprofen and about26.6 mg famotidine, two unit dosage forms containing 400 mg ibuprofenand about 13.3 mg famotidine, or even four unit dosage forms containing200 mg ibuprofen and about 7 mg famotidine. Preferably, atherapeutically effective dose is administered as one or two tablets.

The therapeutically effective amount of ibuprofen so administered isusually in the range 50 mg to 1000 mg. A therapeutically effective dosefor headache or mild pain may be 200 mg or 400 mg TID. A therapeuticallyeffective dose for arthritis is usually 800 mg TID.

In general, the unit dosage forms of the invention comprise ibuprofen inan amount of about 50-1000 mg. In certain embodiments the unit dosageform comprises ibuprofen in an amount of about 200-800 mg, about 300-500mg, about 700-800 mg, about 400 mg or about 800 mg ibuprofen.

For many applications the quantity of ibuprofen in the unit dose form isabout 800 mg (e.g., in the range 750 mg to 850 mg) which allowsadministration of 2400 mg/day with TID administration of one tablet, orthe quantity of ibuprofen is about 400 mg (e.g., in the range 375 mg to425 mg) which allows administration of 2400 mg/day with TIDadministration of two tablets.

The therapeutically effective amount of famotidine so administered isusually in the range 7 mg to 30 mg. In general, the unit dosage forms ofthe invention comprise famotidine in the range of 12 mg to 28 mg. Formany applications the quantity of famotidine in the unit dose form isabout 26.6 mg (e.g., in the range 24 mg to 28 mg) which allowsadministration of 80 mg/day with TID administration of one tablet, orthe quantity of famotidine is about 13 mg (e.g., in the range 12 mg to14 mg) which allows administration of 80 mg/day with TID administrationof two tablets.

In one preferred embodiment, the oral unit dosage forms are formulatedto deliver a daily dose of about 2400 mg ibuprofen and about 80 mgfamotidine with three times per day administration. For manyapplications the quantity of ibuprofen is about 800 mg (e.g., in therange 750 mg to 850 mg) and the quantity of famotidine is about 26.6 mg(e.g., in the range 24 mg to 28 mg). This allows administration of 2400mg/day ibuprofen and 80 mg/day famotidine with TID administration of onetablet. In a related embodiment, the quantity of ibuprofen is about 400mg (e.g., in the range 375 mg to 425 mg) and the quantity of famotidineis about 13 mg (e.g., in the range 12 mg to 14 mg). This allowsadministration of 2400 mg/day ibuprofen and 80 mg/day famotidine withTID administration of two tablets. In a related embodiment, the quantityof ibuprofen is about 200 mg (e.g., in the range 175 mg to 225 mg) andthe quantity of famotidine is about 6.6 mg (e.g., in the range 6 mg to 7mg).

In one embodiment, the oral unit dosage forms are formulated to delivera daily dose of about 1800 mg ibuprofen and about 80 mg famotidine withthree times per day administration. For many applications the quantityof ibuprofen is about 600 mg (e.g., in the range 550 mg to 650 mg) andthe quantity of famotidine is about 26.6 mg (e.g., in the range 24 mg to28 mg). This allows administration of 1800 mg/day ibuprofen and 80mg/day famotidine with TID administration of one tablet. In a relatedembodiment, the quantity of ibuprofen is about 300 mg (e.g., in therange 275 mg to 325 mg) and the quantity of famotidine is about 13 mg(e.g., in the range 12 mg to 14 mg). This allows administration of 1800mg/day ibuprofen and 80 mg/day famotidine with TID administration of twotablets.

In other embodiments more or less API may be administered. For example,in some cases the daily dose of ibuprofen is greater than 2400 mg (e.g.,3200 mg). This amount can easily be administered as, for example, threeor six tablets per day, particularly using an ibuprofen formulation thatcan be tabletted with little excipient (e.g., BASF Ibuprofen DC 85®). Ifa formulation that contains only the active S-enantiomer of ibuprofen isused, a smaller quantity may sometimes be administered (e.g., an amountthat produces the same therapeutic effect as a therapeutic dose of theracemic mixture).

In certain embodiments the ratio of ibuprofen to famotidine in thedosage forms of the invention is in the range of 15:1 to 40:1, moreoften 20:1 to 40:1, and even more often 25:1 to 35:1. In someembodiments the ratio of ibuprofen to famotidine in the dosage forms ofthe invention is in the range of 29:1 to 32:1, such as 30:1 to 31:1. Inone embodiment the ratio of ibuprofen to famotidine is about 30:1.Exemplary amounts of ibuprofen and famotidine include 800±10% mgibuprofen and 26.6±10% mg famotidine; 400±10% mg ibuprofen and 13.3±10%mg famotidine; and 200±10% mg ibuprofen and 6.65±10% mg famotidine.

In certain embodiments the ratio of ibuprofen to famotidine in thedosage forms of the invention is in the range of range of 20:1 to 25:1,such as 22:1 to 23:1. In one embodiment the ratio of ibuprofen tofamotidine is about 22.5:1. Exemplary amounts of ibuprofen andfamotidine include 600±10% mg ibuprofen and 26.6±10% mg famotidine.

In a preferred embodiment, the oral dosage form does not contain apharmaceutically active compound (i.e., drug compound) other thanibuprofen and famotidine. In particular embodiments the oral dosage formdoes not contain any NSAID other than ibuprofen and/or does not containany H2-receptor antagonist other than famotidine. In certain embodimentsthe amount of famotidine is other than 5 mg, other than 10 mg, otherthan 20 mg or other than 40 mg per dosage form.

9.2 Rapid Release of Famotidine and Ibuprofen

In certain embodiments oral dosage forms of the invention are formulatedso that release of both APIs occurs (or begins to occur) at about thesame time. “At about the same time” means that release of one API beginswithin 5 minutes of the beginning of release of the second API,sometimes with 4 minutes, sometimes within 3 minutes, sometimes within 2minutes, and sometimes essentially simultaneously. “At about the sametime” can also mean that release of one API begins before release of thesecond API is completed. That is, the dosage form is not designed sothat one of the APIs is released significantly later than the other API.For example, the barrier layer (described below), if present, is notdesigned to significantly delay release of the API contained within it.Combinations of excipients (which may include one or more of a binder, alubricant, a diluent, a disintegrant, a glidant and other components)are selected which do substantially retard release of an API. See e.g.,HANDBOOK OF PHARMACEUTICAL MANUFACTURING FORMULATIONS, 2004, Ed.Sarfaraz K Niazi, CRC Press; HANDBOOK OF PHARMACEUTICAL ADDITIVES,SECOND EDITION, 2002, compiled by Michael and Irene Ash, Synapse Books;and REMINGTON SCIENCE AND PRACTICE OF PHARMACY, 2005, David B. Troy(Editor), Lippincott Williams & Wilkins.

In some embodiments both the famotidine or ibuprofen are formulated forimmediate release, and not for release profiles commonly referred to asdelayed release, sustained release, or controlled release. For example,in an embodiment the unit dosage form is formulated so that famotidineand ibuprofen are released rapidly under neutral pH conditions (e.g., anaqueous solution at about pH 6.8 to about pH 7.4, e.g., pH 7.2). In thiscontext “rapidly” means that both APIs are significantly released intosolution within 20 minutes under in vitro assay conditions. In someembodiments both APIs are significantly released into solution within 15minutes under in vitro assay conditions. In this context, “significantlyreleased” means that at least about 60% of the weight of the API in theunit dosage form is dissolved, preferably at least about 75%, morepreferably at least about 80%, often at least 90%, and sometimes atleast about 95%. In one embodiment, both famotidine and ibuprofen are atleast 95% released in 30 minutes.

Dissolution rates may be determined using known methods. Generally an invitro dissolution assay is carried out by placing thefamotidine-ibuprofen unit dosage form(s) (e.g., tablet(s)) in a knownvolume of dissolution medium in a container with a suitable stirringdevice. Samples of the medium are withdrawn at various times andanalyzed for dissolved active substance to determine the rate ofdissolution. Dissolution may be measured as described for ibuprofen inthe USP or, alternatively, as described for famotidine in the USP. Oneapproach is illustrated in Example 6. Briefly, the unit dose form (e.g.,tablet) is placed in a vessel of a United States Pharmacopeiadissolution apparatus II (Paddles) containing 900 ml dissolution mediumat 37° C. The paddle speed is 50 RPM. Independent measurements are madefor at least three (3) tablets. In one suitable in vitro assay,dissolution is measured using a neutral dissolution medium such as 50 mMpotassium phosphate buffer, pH 7.2 (“neutral conditions”) generally asdescribed in Example 6, below.

9.3 Substantial Release of Famotidine and Ibuprofen Under Low pHConditions

In an embodiment the unit dosage form is formulated so that famotidineand ibuprofen are both released rapidly under low pH conditions. Releaseunder low pH conditions is measured using the assay described above andin Example 6, but using 50 mM potassium phosphate buffer, pH 4.5 as adissolution medium. As used in this context, the APIs are releasedrapidly at low pH when a substantial amount of both APIs is releasedinto solution within 60 minutes under low pH assay conditions. In someembodiments, a substantial amount of both APIs is released into solutionwithin 40 minutes under low pH assay conditions. In some embodiments, asubstantial amount of both APIs is released into solution within 20minutes under low pH assay conditions. In some embodiments, asubstantial amount of both APIs is released into solution within 10minutes under low pH assay conditions. In this context, a “substantialamount” means at least 15%, preferably at least 20%, and most preferablyat least 25% of ibuprofen is dissolved and at least 80%, preferably atleast 85%, and most preferably at least 90% of famotidine is dissolved.

9.4 Gastric Protection

As illustrated in Examples 1 and 2, TID administration to a subject offamotidine results in an intragastric pH that is elevated (in magnitudeand/or duration), on average, relative to the intragastric pH resultingfrom conventional BID administration of famotidine, resulting in bettergastric protection. As used herein administration of a pharmaceuticalcomposition or compositions “provides better gastric protection”compared to administration of a reference composition or compositionswhen administration of the pharmaceutical composition maintains stomachpH at a more basic level. It has now been discovered that TIDadministration of famotidine provides better gastric protection thanconventional BID dosing of the same daily dose of drug.

Intragastric pH can be determined by art-known methods using, forexample, a nasogastric pH probe. One useful probe is the Digitrapper™ pH400 ambulatory pH recorder from Medtronic Functional Diagnostics(Shoreview, Minn.). Typically pH is measured several times minute (e.g.,the Digitrapper™ pH 400 makes measurements at a frequency of ¼ Hz) andthe median pH over a 24 hour period is calculated. Measurements can becalculated for specific periods (e.g., upright, sleeping, postprandial,etc). Measurements can be made after the subject has received theappropriate dosage regimen for 1, 2 or 3 days or longer than 3 days,such as after several weeks of use.

An individual in need of ibuprofen treatment and receivingibuprofen-famotidine combination therapy will have greater gastricprotection when a unit dose containing famotidine (or containing afamotidine plus ibuprofen combination) is administered TID. Similarly,in a group of treated individuals in which responses are somewhatvariable, an individual may have a reduced likelihood of gastric damage(e.g., exposure to low pH) when an ibuprofen-famotidine unit dose formis administered TID. The individual (or individuals in a group) may insome cases have shared characteristics. In general the individual orindividuals (hereinafter, “individual”) is an adult (over 18 years ofage). In one embodiment the individual is male. In one embodiment theindividual is female. In one embodiment the individual has an age in therange 19-42 years. In various embodiments the individual may have an agein years in the range of 20-30, 25-35, 30-40, 35-45, 40-50, 45-55,50-60, 55-65, 60-70 or older than 70 years old. In one embodiment theindividual has a normal weight (i.e., a Body Mass Index of 20-25). Inone embodiment the individual does not have a normal body weight (i.e.,BMI <20 or BMI >25).

Gastric protection can be measured in a single individual or in a groupof individuals (a “patient population”). Measurements can be made in aspecified group of individuals to measure gastric protection (e.g., todetermine the median gastric pH) and the median of the measure ofgastric protection (e.g., time with gastric pH >4; median pH over 24hour period, etc.) determined. In one embodiment the individuals in thegroup are male. In one embodiment the individuals in the group arefemale. In one embodiment the group includes both male and femaleindividuals. In one embodiment the group includes both individuals undertreatment for RA. In various embodiments the individuals in the groupmay have an age in years in the range of 19-42, 20-30, 25-35, 30-40,35-45, 40-50, 45-55, 50-60, 55-65, 60-70 or older than 70 years old. Inone embodiment the individuals in the group have a normal weight (i.e.,a Body Mass Index of 20-25). In another embodiment, a patient populationis a group of patients who are under the care of the same doctor orhealthcare provider or receive treatment at the same health carefacility or obtain therapeutics at the same pharmacy.

9.4.1 Fraction of 24-Hour Dosing Cycle with pH Above a Specified Value

One measure of gastric protection is the fraction of a 24-hour dosingcycle during which amount of time pH is maintained above a designatedvalue (e.g., pH 2.5, pH 3.0, pH 3.5, pH 4.0, or pH 4.5). For example,better gastric protection can be characterized as pH above thedesignated value for more time in a 24 hour dosing cycle thanadministration of the reference composition(s). TID administration offamotidine (or, alternatively a unit dosage form of the inventioncontaining famotidine and ibuprofen) will maintain gastric pH of 2.5 orgreater for at least 5, at least 6, at least 7, at least 8, at least 9,at least 10, at least 11, at least 12, at least 13, at least 14, atleast 15, at least 16, at least 17, at least 18, at least 19, at least20, at least 21, at least 22, or at least 23 hours of a 24 hour dosingcycle. In one embodiment, TID administration of famotidine (or,alternatively a unit dosage form of the invention containing famotidineand ibuprofen) will maintain a gastric pH of 3.0 or greater for at least5, at least 6, at least 7, at least 8, at least 9, at least 10, at least11, at least 12, at least 13, at least 14, at least 15, at least 16, atleast 17, at least 18, at least 19, at least 20, at least 21, at least22, or at least 23 hours of a 24 hour dosing cycle. In one embodiment,TID administration of famotidine (or, alternatively a unit dosage formof the invention containing famotidine and ibuprofen) will maintain agastric pH of 3.5 or greater for at least 5, at least 6, at least 7, atleast 8, at least 9, at least 10, at least 11, at least 12, at least 13,at least 14, at least 15, at least 16, at least 17, at least 18, atleast 19, at least 20, at least 21, at least 22, or at least 23 hours ofa 24 hour dosing cycle. In one embodiment, TID administration offamotidine (or, alternatively a unit dosage form of the inventioncontaining famotidine and ibuprofen) will maintain a gastric pH of 4.0or greater for at least 5, at least 6, at least 7, at least 8, at least9, at least 10, at least 11, at least 12, at least 13, at least 14, atleast 15, at least 16, at least 17, at least 18, at least 19, at least20, at least 21, at least 22, or at least 23 hours of a 24 hour dosingcycle. TID administration of famotidine (or, alternatively a unit dosageform of the invention containing famotidine and ibuprofen) will maintaingastric pH of 4.5 or greater for at least 5, at least 6, at least 7, atleast 8, at least 9, at least 10, at least 11, at least 12, at least 13,at least 14, at least 15, at least 16, at least 17, at least 18, atleast 19, at least 20, at least 21, at least 22, or at least 23 hours ofa 24 hour dosing cycle. In one embodiment of the present invention, TIDadministration of famotidine (or, alternatively TID administration aunit dosage form of the invention containing famotidine and ibuprofen)results in a gastric pH above a specified value (e.g., at least 2.5, atleast 3.0, at least 3.5, at least 4.0 or at least 4.5) for more time ina 24-hour dosing cycle that than BID administration of the same dailydose of famotidine (or, alternatively a BID administration of the samedaily dose of famotidine and TID administration of the same daily doseof ibuprofen) where the difference is (in minutes) at least 10, at least20, at least 30, at least 40, or at least 50, at least 60, at least 120,at least 180, at least 240, at least 300 or more.

9.4.2 Minimum Sustained Gastric pH

Another measure of gastric protection is the minimum sustained gastricpH during a 24-hour dosing cycle. “Sustained pH” refers to a gastric pH(or pH range) sustained for at least 10 minutes. Better gastricprotection can be characterized as a higher minimum sustained pH whenmeasured over a 24-hour dosing period. In one embodiment of the presentinvention, TID administration of famotidine (or, alternatively a unitdosage form of the invention containing famotidine and ibuprofen)results in a minimum sustained pH of at least 2.0, preferably at least2.3, more preferably at least 2.5, and sometimes at least 3.0. In oneembodiment of the present invention, TID administration of famotidine(or, alternatively TID administration a unit dosage form of theinvention containing famotidine and ibuprofen) results in a minimumsustained pH that is higher than BID administration of the same dailydose of famotidine (or, alternatively a BID administration of the samedaily dose of famotidine and TID administration of the same daily doseof ibuprofen) where the difference in pH is at least 0.2, at least 0.4,at least 0.5, at least 0.6, or at least 0.7 pH units.

9.4.3 Median Gastric pH

Another measure of gastric protection is the median gastric pH during a24-hour dosing cycle. Better gastric protection can be characterized asa higher median gastric pH over a 24-hour dosing period. In oneembodiment of the present invention, TID administration of famotidine(or, alternatively a unit dosage form of the invention containingfamotidine and ibuprofen) results in a median gastric pH of at least2.5, at least 2.6, at least 2.7, at least 2.8, at least 2.9, at least3.0, at least 3.1, at least 3.2, at least 3.3, at least 3.4, at least3.5, at least 3.6, at least 3.7, at least 3.8, at least 3.9, at least4.0, at least 4.1, at least 4.2, at least 4.3, at least 4.4, at least4.5, at least 4.6, at least 4.7, at least 4.8, at least 4.9, at least5.0, at least 5.1, at least 5.2, at least 5.3, at least 5.4, at least5.5, at least 5.6, at least 5.7, at least 5.8, at least 5.9, at least6.0, at least 6.1, at least 6.2, at least 6.3 or at least 6.4.

In one embodiment of the present invention, TID administration offamotidine (or, alternatively TID administration a unit dosage form ofthe invention containing famotidine and ibuprofen) results in a mediangastric pH that is higher than BID administration of the same daily doseof famotidine (or, alternatively a BID administration of the same dailydose of famotidine and TID administration of the same daily dose ofibuprofen) where the difference in pH is at least 0.2, at least 0.3, atleast 0.4, at least 0.6, at least 0.7 or at least 0.8 pH units.

For illustration, TID administration of a unit dosage form containing800 mg ibuprofen and 26.6 mg famotidine would provide superior gastricprotection than does TID administration of a unit dosage form containing800 mg ibuprofen and BID administration of a unit dosage form containing40 mg famotidine.

9.5 Reduced Patient-to-Patient Variability

As shown in Example 2, interpatient variability in gastric pH wassignificantly reduced when subjects received 80 mg/day famotidine asthree 26.7 mg doses (TID administration) compared to two 40 mg doses(BID administration).

It is known that there may be considerable patient-to-patientvariability in the effects of drugs or drug combination administered toa population of patients. This interpatient variability complicates thetreatment of many disorders, and identifying methods to reduceside-effects (toxicity) and maximize effectiveness in a diversepopulation is challenging. In the case of subjects receiving ibuprofenand famotidine treatment in combination, the interpatient variationmeans that some patients have heightened susceptibility to side-effectsresulting from low gastric pH. Methods that reduce interpatientvariability should therefore reduce the incidence of side-effects in thetreated population. That is, reducing inter-patient variability in agroup reduces the risk that any particular individual in the group willexperience detrimental gastric pH.

In one aspect, the present invention provides a method for reducinginterpatient variability with respect to gastric pH in a population ofpatients receiving an ibuprofen-famotidine combination treatment, byadministering an oral dosage form containing a therapeutically effectiveamount of ibuprofen and a therapeutically effective amount offamotidine, where the oral dosage form is administered three times perday (TID). In one embodiment the population of patients in whichinterpatient variability is reduced comprises all patients in need of orreceiving ibuprofen-famotidine combination therapy. In this context,“ibuprofen-famotidine combination therapy” refers to administration ofibuprofen and famotidine as part of the same course of treatment which,as noted above, generally involves administration of ibuprofen TID andadministration of famotidine BID. In other embodiments the population ofpatients in which interpatient variability is reduced comprises asubpopulation of patients in need of or receiving ibuprofen-famotidinecombination therapy such as individuals having a Body Mass Index in therange of 20-25 and/or having an age in years in the range of 19-42,20-30, 25-35, 30-40, 35-45, 40-50, 45-55, 50-60, 55-65, or 60-70.

The observed reductions in interpatient variability provides importantclinical benefits. These important clinical benefits include fewerpatients who experience a daily median pH below 2.5 It is believepatients experiencing a median pH below 2.5 are at higher risk forgastric acid-induced ulceration when treated TID compared to BID dosing.Notably, as discussed in Example 2, infra, in a clinical study a 24-hourmedian gastric pH was below 2.5 for three patients when receivingfamotidine on a BID schedule, but no patients when receiving famotidineon a TID schedule.

10.0 Exemplary Unit Dose Forms

Oral dosage forms of the invention may have a variety of designs,provided the ibuprofen and the famotidine are in separate compartmentsof the oral dosage form.

In some embodiments, the ibuprofen and the famotidine compartments areseparated by a barrier layer. In some embodiments, the inventionprovides a solid oral dosage form with a first portion comprising atherapeutically effective amount of ibuprofen and a second portioncomprising a therapeutically effective amount of famotidine, where theibuprofen portion completely surrounds the famotidine portion or thefamotidine portion completely surrounds the ibuprofen portion; and abarrier layer disposed between the two portions.

The API content of the unit dose forms is selected so that TIDadministration delivers a therapeutically effective dose of ibuprofenand a therapeutically effective dose of famotidine. Preferably the oraldosage form comprises ibuprofen and famotidine in the amounts and ratiosdescribed herein.

According to the invention, famotidine and ibuprofen are releasedrapidly, as described above. It will be recognized, therefore, that inthis aspect of the invention neither the dosage nor the APIsindividually are enteric coated or formulated for sustained or delayedrelease. The tablets are formulated so that they disintegrate in thestomach after they are swallowed and do not dissolve in the mouth orthroat during the normal process of oral administration. Otherproperties of the oral dosage forms of the invention will be apparent tothe reader.

With these properties in mind, exemplary oral dosage forms are describedbelow, for illustration and not for limitation. It will be understoodthat many other forms may be made by one of skill in the art guided bythis disclosure, and that information related to one dosage form below(e.g., a description of excipients) may be used in connection with otherforms.

10.1 Exemplary Oral Dosage Form I

In one version, the oral dosage form comprises an ibuprofen core(“core”), a surrounding layer containing famotidine (“famotidine layer”)and a barrier layer interposed between the core and famotidine layer. Inone embodiment famotidine coat entirely surrounds the ibuprofen core.Optionally the tablet is coated by one or more over-coating layers, forexample, to improve appearance, taste, swallowability, or for otherreasons. Methods for formulation and manufacture of pharmaceutical unitdose forms are known in the art, see, e.g., HANDBOOK OF PHARMACEUTICALMANUFACTURING FORMULATIONS, 2004, Ed. Sarfaraz K Niazi, CRC Press;HANDBOOK OF PHARMACEUTICAL ADDITIVES, SECOND EDITION, 2002, compiled byMichael and Irene Ash, Synapse Books; and REMINGTON SCIENCE AND PRACTICEOF PHARMACY, 2005, David B. Troy (Editor), Lippincott Williams &Wilkins. One of ordinary skill in the art guided by this disclosure willbe able to make a variety of suitable oral unit dose forms.

10.1.1 The Ibuprofen Core of Exemplary Oral Dosage Form I

The ibuprofen core may vary in shape and may be, for example, round,ovoid, oblong, cylindrical (e.g., disk shaped) or any other suitablegeometric shape, for example rectilinear. Preferably the tablet has adisk or ovoid shape is shaped like a flattened disk, ovoid or torpedo.The edges of the tablets may be beveled or rounded. The tablet may alsobe shaped as a caplet (capsule form tablet). The tablets may be scored,embossed or engraved. In one embodiment, the core does not have aninternal hole extending all or part-way through the pill. For example,in one embodiment the core is not shaped like a cup or donut.

The tablet of the invention comprises a therapeutically effective amountof ibuprofen API. This is usually in the range 50 mg to 1000 mg. Formany applications the quantity of ibuprofen is about 800 mg (e.g., inthe range 750 mg to 850 mg, or in the range 775-825 mg) which allowsadministration of 2400 mg/day with TID administration of one tablet, orthe quantity of ibuprofen is about 400 mg (e.g., in the range 375 mg to425 mg) which allows administration of 2400 mg/day with TIDadministration of two tablets. In addition to ibuprofen the core maycontain excipients such as one or more disintegrants, binders, glidants,or lubricants. For example, the core may contain lactose (e.g., lactosemonohydrate); colloidal silicon dioxide; sodium croscarmellose; hydroxypropyl methyl cellulose; silicified microcrystalline cellulose and/ormagnesium stearate. In one embodiment ibuprofen core comprisesibuprofen, 20-30% (w/w) lactose monohydrate; 0.1 to 2% colloidal silicondioxide; 3-7% crosscarmellose sodium; 1-3% hydroxy propyl methylcellulose; 2-6% silicified microcrystalline cellulose (e.g., ProsolvSMCC 90) and 0.1-2% magnesium stearate. In some embodiments, the coredoes not contain a lubricant.

In one embodiment, the core comprises Ibuprofen DC 85 (BASF) whichcomprises 85% API, or a similar directly compressible ibuprofenformulation described in WO 2007/042445 (i.e., an ibuprofen formulationcomprising 50 to 99% by weight crystalline ibuprofen, 1 to 15% of ahighly dispersible adjuvant having a minimum surface of 100 m²/g,wherein at least 50% of the surface of the ibuprofen crystals is coatedwith the highly dispersible adjuvant, and 0 to 40% other adjuvants.Exemplary formulations using Ibuprofen DC 85, for illustration and notlimitation, include:

-   -   1) Ibuprofen DC 85 (88.24% w/w); microcrystalline cellulose        (7.76%); crosslinked sodium carboxymethylcellulose (3.00%);        silica (0.05%); and magnesium stearate (0.50%);    -   2) Ibuprofen DC 85 (88.24% w/w); corn starch (7.76%);        crosslinked sodium carboxymethylcellulose (3.00%); silica        (0.05%) and magnesium stearate (0.50%);    -   3) Ibuprofen DC 85 (88.24% w/w); lactose (7.76%); crosslinked        sodium carboxymethylcellulose (3.00%); silica (0.05%) and        magnesium stearate (0.50%).

The core may be formed using art-known techniques including wetgranulation, dry granulation, direct compression or any otherpharmaceutically acceptable process. The appropriate amount of theibuprofen formulation (i.e., the amount containing the unit dose of API)may be compression pressed into individual cores. Alternatively, thecore may be formed by molding.

In one embodiment, the core portion is at least 50% ibuprofen by weight,preferably at least 60%, and more preferably at least 70%, and even morepreferably at least 80% ibuprofen.

10.1.2 The Barrier Layer of Exemplary Oral Dosage Form I

The barrier layer may be composed of any of a variety of materials that(1) separate the core and famotidine layer and (2) rapidly disintegratein an aqueous (e.g., gastric) environment so that the ibuprofen israpidly released.

The barrier layer may comprise fillers, binders, disintegrants,lubricants, glidants, and the like, as known in the art. Suitablefillers for use in making the barrier layer, or a portion thereof, bycompression include water-soluble compressible carbohydrates such assugars, which include dextrose, sucrose, maltose, and lactose,sugar-alcohols, which include mannitol, sorbitol, maltitol, xylitol,starch hydrolysates, which include dextrins, and maltodextrins,

In one embodiment, the ibuprofen cores are coated with Opadry II™ white(Colorcon Y-22-7719) according to manufacturer's instructions to aweight gain of 1.5-2.0% w/w. Other known barrier layer materials includehydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,and cellulose acetate phthalate. In one embodiment, the barrier layerformulation will contain at least one coating layer polymer and acoating solvent (preferably water) used for processing and removed bydrying. The coating layer polymer may be hydroxypropyl methylcellulose,polyvinyl alcohol (PVA), ethyl cellulose, methacrylic polymers orhydroxypropyl cellulose. A plasticizer (e.g., triacetin, diethylphthalate, tributyl sebacate or polyethylene glycol) may also beincluded. The coating layer may include an anti-adherent or glidant(e.g., talc, fumed silica or magnesium stearate) and colorants such astitanium dioxide, iron oxide based colorants or others.

The thickness of the barrier layer can vary over a wide range, but isgenerally in the range 20 to 3,000 microns, such as on the order ofabout 25 to 250 microns. Preferably the barrier layer retards therelease of API by less than 5 minutes, preferably less than 4 minutesand more preferably by less than 3 minutes.

The barrier layer may be formed by any method, including compression,molding, dipping, or spray coating.

10.1.3 The Famotidine Layer of Exemplary Oral Dosage Form I

The famotidine layer is applied over the barrier coat. The famotidinelayer can be applied by compression, spray coating, or other methods. Ina preferred embodiment, the famotidine layer is applied by spray coatinga formulation containing famotidine and excipients such as polymers,plasticizers, and the like. In one example, famotidine is combined withOpadry II (Colorcon) and spray coated over the ibuprofen core or barrierlayer.

The dosage form of the invention comprises a therapeutically effectiveamount of famotidine API. For many applications the quantity offamotidine is about 26.6 mg (e.g., in the range 24 mg to 28 mg) whichallows administration of 80 mg/day with TID administration of onetablet, or the quantity of famotidine is about 13 mg (e.g., in the range12 mg to 14 mg) which allows administration of 80 mg/day with TIDadministration of two tablets.

10.1.4 Over Coating Layers of Exemplary Oral Dosage Form I

In some embodiments, the tablets are coated for oral administration, tomake the tablet easier to swallow, to mask taste, for cosmetic reasons,or for other reasons. Coating of tablets and caplets is well known inthe art. Coating systems are typically mixtures of polymers,plasticizers, coloring agents and other excipients, which can be stirredinto water or an organic solvent to produce a dispersion for the filmcoating of solid oral dosage forms such as tablets.

Usually a readily soluble film is used. Materials that can be used forreadily soluble films include cellulose derivatives (such ashydroxypropylmethyl cellulose) or amino-alkylmethacrylate copolymers(e.g. EudragitTME). Suitable coat layers, for illustration and notlimitation, include Kollicoat® IR (a polyvinyl alcohol-polyethyleneglycol graft copolymer) and Kollicoat IR White® both manufactured byBASF Aktiengesellschaft (Ludwigshafen, Germany).

10.2 Exemplary Oral Dosage Form II

In one version, the oral dosage form comprises many small particles ofibuprofen, each coated with a barrier layer, with the particles situatedin a matrix or medium containing famotidine. The barrier layers may bemade as described above (e.g., using Kollicoat™, Opadry™ or similarmaterials). In this version the particles may have a variety of sizes,ranging from a mean or average size of 200 microns to 2000 microns ormore. For example, and not for limitation, the mean size can be in therange 200-1500, 600-700, 700-800, 800-900, 900-1000, 1100-1200,1200-1300, 1300-1400, 1400-1500, 1500-1600, 1600-1700, 1700-1800,1800-1900, 1900-2000 microns or more. In one embodiment at least 80%,and more often at least 90% of the particles are in the size range of350-800 microns. In some embodiments a mixture of particle sizes isused. The ibuprofen particles may be contained in or distributed in amatrix containing famotidine. The matrix can include binders,lubricants, diluents, disintegrants, and other components known in theart. As used in this context, the term “matrix” does not connotate anyparticular structure.

In one version, the ibuprofen particles can be contained in a capsulethat also contains famotidine and suitable excipients or carriers.

10.3 Exemplary Oral Dosage Form III

In one version, the oral dosage form comprises many small particles offamotidine coated with a barrier layer and situated in a matrixcontaining ibuprofen. The barrier layers may be made as described above(e.g., using Opadry or similar materials). In certain versions, theparticles may have a variety of sizes, ranging from a mean or averagesize of 100 microns to 2000 microns or more. For example, and not forlimitation, the particles can be in the range 200-800, 200-600, 200-400,350-800, or 350-600. In some embodiments a mixture of particle sizes isused. The matrix or tablet can include binders, lubricants, diluents,disintegrants, and other components known in the art. In one embodimentthe matrix consists primarily of ibuprofen. In one embodiment theibuprofen is Ibuprofen DC 85™ (BASF). In one version, the famotidineparticles can be contained in a capsule that also contains ibuprofen andsuitable excipients or carriers.

In one version, the unit dose form comprises coated famotidine particlesmixed with ibuprofen (which may be Ibuprofen DC 85™) and compressed intotablets. In one approach the coated famotidine particles are prepared byspray granulating famotidine onto a carrier particles, coating theresulting granule with a barrier layer, and optionally a furtherprotective layer.

In certain embodiments, the carrier particles may be an inert materialsuch as microcrystalline cellulose (fine grade; e.g., Avicel PH101 [FMCCorp.]), or the like. The famotidine may be spray granulated onto thecarrier particles in any suitable manner, e.g., in a fluid bedprocessor, using a solution of famotidine, an optional film former, anoptional anti-static agent, and other optional excipients and diluents.For instance, Opadry II® or similar materials, e.g., such as thosedescribed in U.S. Pat. No. 4,802,924, incorporated herein by reference,may be used as a film former, and talc or similar inert material may beused as an anti-static agent. By way of non-limiting example, thefamotidine spray mixture may comprise about 75% active, about 20% filmformer, and about 5% anti-static agent, by weight.

The famotidine spray mixture is coated onto the inert material until thedesired amount of famotidine is added, such as a weight gain perparticle or on a batch basis of 20% to 200%. For example, the 1.25 partsfamotidine mixture can be sprayed on 1 part microcrystalline celluloseto a weight gain of about 90% to 110% (i.e., about 100%).

A barrier layer may be applied over the famotidine coated granules.Again, the barrier layer of the famotidine particles may be made asdescribed above (e.g., using Opadry®, Kollicoat®, or similar materials).In certain embodiments, the barrier layer may be applied to about a5-50% weight gain per particle or on a batch basis, e.g., a 20% weightgain.

In certain embodiments, the optional polymeric protective coating may beapplied to about a 5%, 10%, 20%, or more than 20% weight gain perparticle on a batch basis, depending on the degree of protectiveelastic/compressibility properties desired.

The resulting famotidine granules are preferably large enough forconvenient handling and to maximize content uniformity of the resultingunit dose forms. In some embodiments the famotidine granules are in thesize range of 100 microns to 1000 microns, such as in the range of350-800 microns. Particle size is usually determined based on theability of particles to pass through an opening (e.g., using a US sieveseries, or Tyler equivalent mesh). In one embodiment at least about 80%,and usually at least 90%, of the famotidine particles are in the sizerange of less than 800 microns, e.g., 350-800 microns.

Particle size can be determined by microscopy, laser diffraction,dynamic light scanning (DLS), sieve analysis, or other methods. In apreferred embodiment particle size is determined by sieve analysis.Sieve analysis methods are routine in the art. For example, sieveanalysis can be preformed using an ATM sonic sifter. The equipment maybe set to run for 10 minutes with sift and pulse at amplitude #6. Sievesmay be nested in the following order: #20 mesh (850 microns), #20 mesh(420 microns), #60 mesh (250 microns), #120 mesh (125 microns), #325mesh (45 microns), and fines pan (<45 microns). Samples are run induplicate and the generated percent retained reflect the average of thetwo measurements

The famotidine particles may then be blended with ibuprofen granules andcompressed into tablets in any suitable method known in the art.Optionally a lubricant, such as magnesium stearate, may be added to theibuprofen-famotidine mixture prior to the compression step.

In one version the ibuprofen is in the form of granules with a meanparticle size under 100 microns (e.g., 25, 38, 50, or 90 microns).Suitable ibuprofen preparations are available from BASFAktiengesellschaft, Ludwigshafen, Germany. In one version the ibuprofenis in the form of an ibuprofen containing active agent preparation asdescribed in patent publication US 20030045580 (assigned to BASF A.G.).In one version the ibuprofen is in the form of an ibuprofen preparationas described in patent publication US 20050003000 (assigned to BASFA.G.). In one version, the unit dose form contains coated famotidinegranules, ibuprofen and excipients. Excipients may include binders(e.g., SMCC), lubricants (e.g., magnesium stearate), diluents,disintegrants (e.g., croscarmellose), coatings, barrier layercomponents, glidants (e.g., colloidal silicon dioxide). In one version anonionic surfactant having an hydrophiliclipophilic balance (HLB) of atleast 9 is included in the product (see, e.g., U.S. Pat. No. 6,251,945).

In one version the ibuprofen is in the form of the product DC 85 (BASFAktiengesellschaft, Ludwigshafen, Germany). DC 85 comprises ibuprofen(>80%), silica, croscarmellose sodium and cellulose and is supplied inthe form of granules with a median size of about 700 microns (>90% inthe range 300-1400 microns). Optionally DC 85 are used which have a sizedistribution similar to that of the famotidine granules (e.g., at leastat least about 80%, sometimes at least 90%, and sometimes at least 95%of the DC 85 particles are in the size range of 350-800 microns in anembodiment in which the majority of famotidine particles lie in thatsize range). DC-85 ibuprofen particles of desired size can be obtainedby milling.

In one version, the unit dose form contains coated famotidine granules,DC 85 ibuprofen and a lubricant such as magnesium stearate.

A final coating (e.g., Opadry®, Opadry II®, Kollicoat® or similarmaterials) may be applied using, e.g., a 48″ Accella coata according tomanufacturer's instructions, as generally recognized by those skilled inthe art.

10.4 Exemplary Oral Dosage Form IV

In one version, the oral dosage form comprises many small particles ofibuprofen, each coated with a barrier layer, and many small particles offamotidine each coated with a barrier layer and situated in a matrixcontaining ibuprofen. The barrier layers may be the same or different.The two types of particles can be contained in a matrix or medium togive form to the unit dosage (e.g., tablet).

In one version, the ibuprofen particles and famotidine particles arecontained in a capsule, optionally with excipients or carriers.

10.5 Exemplary Oral Dosage Form V

In one version, the oral dosage form comprises famotidine and IbuprofenDC 85™ (BASF) or famotidine and a coated ibuprofen product madeaccording to the method of U.S. Pat. No. 6,251,945. In this embodiment,a nonionic surfactant coating of the ibuprofen separates the ibuprofenportion from the famotidine portion of the dosage form. In oneembodiment, the unit dosage consists essentially of famotidine,Ibuprofen DC 85™, and optionally an over-coating coat. In otherembodiments, the oral dosage form comprises additional excipients.

10.6 Exemplary Oral Dosage Form VI

In one version, the oral dosage form comprises famotidine and ibuprofenin a bilayer tablet, with famotidine plus excipient in one layer andibuprofen plus excipient in the second layer. Usually the two layers areseparated by a barrier layer. Usually an over-coating is also present.

10.7 Exemplary Oral Dosage Form VII (Admixture Forms)

Exemplary unit dose forms I-VI, above, which are provided forillustration and not limitation, are characterized by having theibuprofen and famotidine APIs in different compartments of the tablet.In an other aspect, unit dose forms of the invention comprise ibuprofen(or other NSAID) in admixture with famotidine and at least oneexcipient. The unit dose form may be a tablet, caplet, gelcap, or otherform. In some embodiments the dosage form includes a core comprising theibuprofen and famotidine, which core is surrounded by an over coatingwhich may be added to improve appearance, taste, swallowability, orother characteristics of the dosage form. It is preferred that the solidformulation of the present invention is durable to usual externalmanipulation yet able dissolve at the acceptable rate.

In one embodiment, the solid tablet carrier contains at least one, andpreferably at least two, of the following components: microcrystallinecellulose, croscarmellose sodium, lactose, magnesium stearate,hydroxypropyl cellulose, starch and talc. For example, the unit doseform may contain one or more of the following excipients: 5-15%microcrystalline cellulose, 0.5-5% croscarmellose sodium, 10-85%lactose, 0.5-5% magnesium stearate, 2-6% hydroxypropyl cellulose, 3-15%pregelatinized starch (e.g. starch 1500), and/or 1-10% talc. In oneembodiment the unit dose form comprises all of the all of the aboveexcipients. It is most preferred, in this embodiment, that the tabletformulation comprises a therapeutically effective amount of ibuprofen orits pharmaceutically acceptable salts, in combination with famotidinewith pharmaceutically acceptable excipients in a pharmacokineticallyeffective ratio. In one embodiment the excipients includemicrocrystalline cellulose 5-15% by weight, croscarmellose sodium 0.5-5%by weight, lactose 10-85% by weight, magnesium stearate 0.5-5% byweight, hydroxypropyl cellulose 2-6% by weight, pregelatinized starch3-15% by weight and talc 1-10% by weight.

In the formulations of the invention, the excipients are present in anamount sufficient to allow for release of the ibuprofen and famotidinefrom the tablet after administration to a subject in need of thistherapeutic combination in a fashion allowing for absorption into theblood at a time and concentration such that the therapeutic effectsmatch that of ibuprofen administered alone and that of famotidineadministered alone. As described in Example 3, it was demonstrated inhuman clinical studies that there are no significant differences betweenthe pharmacokinetic parameters for either ibuprofen or famotidine whenadministered alone compared to administration in combination. It wasconcluded that both ibuprofen and famotidine can be consideredbioequivalent when administered in combination compared to separateadministration.

In a different embodiment, the pharmaceutical composition comprisesmicrocrystalline cellulose 5-10% by weight, croscarmellose sodium 1-4%by weight, lactose 20-75% by weight, magnesium stearate 1-3% by weight,hydroxypropyl cellulose 3-5% by weight, pregelatinized starch 5-10% byweight and talc 2-6% by weight.

In another embodiment, the dosage for comprises 60-80% ibuprofen;1.5-3.0% famotidine; 9-11% microcrystalline cellulose; 2-4% silicifiedmicrocrystalline cellulose; and 0.5-2.5% croscarmellose sodium.

Preferably the formulation comprises 60-80% ibuprofen; 1.5-3.0%famotidine; 9-11% microcrystalline cellulose; 2-4% silicifiedmicrocrystalline cellulose; 1-3% low substitutedhydroxylpropylcellulose; and 0.5-2.5% croscarmellose sodium.

In one embodiment the formulation comprises ibuprofen, famotidine,microcrystalline cellulose, pregelatinized starch, hydroxypropylcellulose, low substituted hydroxypropyl cellulose, silicon dioxide,silicified microcrystalline cellulose, croscarmellose sodium andmagnesium stearate.

In one embodiment the formulation comprises 60-80% ibuprofen; 1.5-3.0%famotidine; 9-11% microcrystalline cellulose; 0.5-1.5% pregelatinizedstarch, 0.2-1% hydroxypropyl cellulose, 1-3% low substitutedhydroxypropyl cellulose, 0.2-1% silicon dioxide, 2-4% silicifiedmicrocrystalline cellulose; 0.5-2.5% croscarmellose sodium, and 0.5-2.9%magnesium stearate.

In one embodiment the formulation comprises 76-78% ibuprofen; 1.5-2.5%famotidine; 9-11% microcrystalline cellulose; 0.5-1.5% pregelatinizedstarch, 0.2-1% hydroxypropyl cellulose, 1-3% low substitutedhydroxypropyl cellulose, 0.2-1% silicon dioxide, 2-4% silicifiedmicrocrystalline cellulose; 0.5-2.5% croscarmellose sodium, and 0.5-2.9%magnesium stearate.

In certain embodiments the microcrystalline cellulose is comprised of afirst population of particles having a median particle size of about 50microns (e.g., EMOCEL 50M) and a second population of particles having amedian particle size of approximately 90 microns (e.g., EMOCEL 90M). Insome embodiments, 50-micron particles are present in at least 10-foldexcess, and sometimes at least a 20-fold excess, over 90-micronparticles.

In certain embodiments the silicified microcrystalline cellulose (SMCC)is comprised of a first population of particles having a median particlesize of about 50 microns (e.g., PROSOLV 50 from Penwest) and a secondpopulation of particles having a median particle size of approximately90 microns (e.g., PROSOLV 90 from Penwest). In one embodiment, the twopopulations are present in approximately equal quantities. Inexperiments inclusion of SMCC and low substituted hydroxypropylcellulosein the formulation resulted in tablets with better compressibility.

In one embodiment the unit dose form has the following composition:

Famotidine 1.5-2.5% Microcrystalline cellulose (median 9-10% particlesize 50 microns) Starch (pregelatinzed) 0.8-10% Hydroxypropyl cellulose0.4-0.8% Ibuprofen 70-80% Colloidal silicon dioxide 0.05-0.10%Microcrystalline cellulose (median 0.2-0.6% particle size 90 microns)Silicified microcystalline cellulose 1-2% (median particle size 50microns) Silicified microcrystalline cellulose 1-2% (median particlesize 90 microns) Low substituted HPC 1-2% Croscarmellose sodium 1-3%Magnesium stearate 2-2.9%

In one embodiment the unit dose form has the following composition:

Famotidine 1.9% Microcrystalline cellulose (median 9.6% particle size 50microns) Starch (pregelatinzed) 0.96% Hydroxypropyl cellulose 0.58%Ibuprofen 76.9% Colloidal silicon dioxide 0.08% Microcrystallinecellulose (median 0.42% particle size 90 microns) Silicifiedmicrocystalline cellulose 1.73% (median particle size 50 microns)Silicified microcrystalline cellulose 1.73% (median particle size 90microns) Low substituted HPC 1.54% Croscarmellose sodium 2.0% Magnesiumstearate 2.5%

In one embodiment the unit dose form has the following composition:

Famotidine 13.3 mg Microcrystalline cellulose (median 50.7 mg particlesize 50 microns) Pregelatinzed starch 5 mg Hydroxypropyl cellulose 3 mgIbuprofen 400.0 mg Colloidal silicon dioxide 0.4 mg Microcrystallinecellulose (median 2.2 mg particle size 90 microns) Silicifiedmicrocystalline cellulose 9.0 mg (median particle size 50 microns)Silicified microcrystalline cellulose 9.0 mg (median particle size 90microns) Low substituted HPC 8.0 mg Croscarmellose sodium 10.4 mgMagnesium stearate 13.0 mg total 524.0 mg

In one embodiment the unit dose form has the following composition:

Famotidine 2.5% Microcrystalline cellulose (e.g., Emcocel ® 50 M) 9.7%Pregelatinzed starch (e.g., Starch 1500) 0.95% Hydroxypropyl cellulose(e.g., Klucel EXF) 0.57% Ibuprofen 90 76.3% Colloidal silicon dioxide0.08% Microcrystalline cellulose (e.g., Emcocel ® 90M) 0.42% Silicifiedmicrocystalline cellulose (e.g., ProSolv 1.72% SMCC ® 50) Silicifiedmicrocrystalline cellulose (e.g., ProSolv 1.72% SMCC ® 90) Lowsubstituted HPC (e.g., LH-11) 1.53% Croscarmellose sodium 2.0% Magnesiumstearate 2.5%

It has been discovered that, under “forced degradation” conditions,ibuprofen and famotidine in admixture are pharmaceutically incompatible.This incompatibility has commercial disadvantages in that tablet contentmay change over time. As shown in Example 4, below, famotidine alone isstable when stored for 2 weeks at 60° C., but is degraded when stored asa mixture with ibuprofen for 2 weeks at 60° C. or for 1 month at 40° C.and 75% relative humidity. Similarly, famotidine degradation is seenwhen a famotidine-ibuprofen admixture in the form of a tablet is stored1 month at 60° C. Surprisingly, however, the tablet form is stable atroom temperature for at least 4 months. This suggests that contrary tothe conclusion that would be drawn from conventional stress testing,ibuprofen-famotidine tablets according to the invention are stable for aprolonged period under normal storage conditions.

10.8 Exemplary Method of Manufacture of an Embodiment of Oral DosageForm I

It is within the ability of one of ordinary skill in the art, guided bythe present disclosure and with reference to the pharmaceuticalliterature, to prepare and manufacture unit dosage forms of theinvention.

For example, for illustration and not for limitation, in one approach anoral dosage form of Form 1 (above) uses wet granulation. A dry mixcontaining ibuprofen, a binder or binders (e.g., lactose monohydrate,hydroxy propyl methyl cellulose), disintegrant (e.g., crosscarmellosesodium) and glidant (e.g., colloidal silicon dioxide) is prepared. Anaqueous solution containing a binder (e.g., hydroxy propyl methylcellulose) is blended with the dry mix. The resulting wet material ismilled and dried to form granules. The granules are blended with binder(e.g., silicified microcrystalline cellulose), disintegrant (e.g.,crosscarmellose sodium), glidant (e.g., colloidal silicon dioxide) andlubricant (e.g., magnesium stearate). The final blend is compressed(e.g., using a DC 16 compression machine) to form the cores.

A barrier coat of Opadry II (Colorcon) is applied by spray coatingaccording to the manufacturer's instructions. For example, one partOpadry II concentrate is added to four parts (by weight) distilled waterwith stirring to form a dispersion. The ibuprofen core tablets areplaced in a rotating pan in a chamber where the temperature ismaintained at 60-70° C. in order to control product temperature at40-45° C. The famotidine-containing coating material is sprayed using aspray gun above the pan. (It can be expected that approximately 75% ofthe famotidine will coat the core, with about 25% lost during thecoating process.) For example, and not for limitation, an Accela-Cota 60inch pan equipped with four mixing baffles rotating at 5 rpm may beused. The spray apparatus may be the Five Spraying Systems 1/4 JAU airgun using 2850 fluid nozzles, 134255-45 aircaps and 60 psi atomizingair. The delivery system may be a pressure pot. The delivery rate may be110 g/min/gun.

A famotidine layer can then be applied. A polymer containing famotidinecan be applied to the coated core by, for example, spray coating orcompression methods known in the art. In one approach, famotidine ismixed with Opadry II (Colorcon) in an about 1:1 ratio and appliedgenerally as described above.

An overcoating layer can then be applied. In one embodiment, after thefamotidine layer is applied, the unit dose forms are coated with OpadryII (Colorcon, Inc. West Point Pa.).

10.9 Exemplary Method of Manufacture of an Embodiment of Admixture OralDosage

A famotidine-ibuprofen tablet having suitable properties can be madeusing a wet granulation process and includes as components ibuprofen,famotidine, microcrystalline cellulose, silicified microcrystallinecellulose, and croscarmellose sodium.

In a related aspect, the invention provides methods for makingibuprofen/famotidine tablets with the above-described content andproperties. In general it is desirable that tablets for oraladministration have a high degree of uniformity as to weight andcontent, have dissolution properties appropriate for the API(s) beingadministered, and are chemically stable.

Methods for preparing tablets from a solid formulation are well known inthe art. Briefly, tablets are usually formed by pressure applied to thematerial to be tabletted on a tablet press. A tablet press includes alower punch which fits into a die from the bottom and an upper punchhaving a corresponding shape and dimension, which enters the die cavityfrom the top after the tabletting material fills the die cavity. Thetablet is formed by pressure applied on the lower and upper punches. Toprepare a tablet containing one or more active ingredients, the mixtureto be compressed into the dosage forms should have certain physicalcharacteristics for processing. Among other things, the mixture to becompressed must be free-flowing, must be lubricated, and must possesssufficient cohesiveness to ensure that the solid dosage form remainsintact after compression. The ability of the material to flow freelyinto the die is important in order to provide for uniform filling of thedie and continuous movement of the material from the source of thematerial, e.g. a feed hopper. The lubricity of the material is importantin the preparation of the solid dosage forms in which the compressedmaterial must be readily ejected from the punch faces.

Thus, compressibility and uniformity are important properties of a soliddosage formulation to be tabletted.

There are three general methods of preparation of materials to beincluded in a solid dosage form prior to compression: (1) directcompression; (2) dry granulation; and (3) wet granulation (includinghigh shear mixer granulation and fluidized bed granulation).

In direct compression procedures, the materials to be included in thesolid dosage form are compressed directly, without modifying thephysical nature of the material itself. For solid dosage forms whereinthe drug itself constitutes a substantial portion of the total weight ofthe solid dosage form, the use of direct compression is limited to thosesituations where the drug itself must exhibit physical characteristics,such as cohesiveness, that make it a good candidate for directcompression with the rest of the ingredients. Tablets containingfamotidine as the sole active ingredient can be manufactured by directcompression. However, this approach is not ideal for manufacturingtablets comprising ibuprofen and famotidine, primarily due to the poorsolubility and low cohesiveness of ibuprofen.

In dry granulation (also called “direct dry mixing”) procedures, thetablet components are mixed, followed by slugging, dry screening,lubricating, and compression into tablets. Dry granulation may be usedwhere one of the constituents, either the drug or the diluent, hassufficient cohesive properties to be tabletted. Tablets made by thisprocess exhibited poor content uniformity for famotidine (84-87%) and apoor dissolution rate for famotidine (92-95% famotidine released after30 minutes in a dissolution test).

Wet granulation procedures includes mixing the powders to beincorporated into a solid dosage form in an appropriate blender (such asa twin shell blender or double-code blender), and then adding solutionsof a binding agent to the mixed powders to obtained a granulation.Thereafter, the damp mass is screened (e.g. in a 6-, 8-, 15-, 25-meshscreen), and dried (e.g. by tray drying, using a fluid-bed dryer, aspray dryer, microwave, vacuum, or infra-red dryer). A wet granulationapproach to preparing ibuprofen/famotidine tablets is described inExamples 3-5 and was shown to be superior. Wet granulation provided apre-compression material with better wetting properties, easingdisintegration and dissolution. In addition, the content uniformity ofthe tablets prepared was improved.

In one aspect, the invention provides a method of making a tabletcomprising ibuprofen and famotidine by:

-   -   a) preparing famotidine granules by wet granulation of 10 parts        famotidine, 50 parts microcrystalline cellulose, 5 parts        pregelatinized starch and 3 parts hydroxylpropyl cellulose,        using water as the liquid, milling and screening the product;    -   b) mixing 400 parts ibuprofen and 0.4 parts colloidal silicon        dioxide to produce intermediate mixture I;    -   c) mixing 2.2 parts microcrystalline cellulose, 9 parts SMCC 50,        9 parts SMCC90, 8 parts low substituted HPC, and 10.4 parts        croscarmellose sodium to produce intermediate mixture II;    -   d) combining the intermediate mixture I and the famotidine        granules incrementally by combining a first portion of        intermediate mixture I with the famotidine granules and mixing,        adding a second portion of intermediate mixture I and mixing,        adding a third portion of intermediate mixture I and mixing, and        optionally combining additional portions, thereby producing        intermediate mixture III;    -   e) combining intermediate mixture II and intermediate mixture        III to produce intermediate mixture IV;    -   f) adding 13 parts magnesium stearate to intermediate IV,        thereby producing a ibuprofen/famotidine solid formulation; and,    -   g) compressing the ibuprofen/famotidine solid formulation to        form tablets.

Using the methods described herein the solid pharmaceutical compositionsof the invention can be formed into tablets with at least about 90%, atleast about 95% or at least about 97% content uniformity.

In one aspect, the invention provides a method of making a tabletcomprising ibuprofen and famotidine by:

-   -   a) preparing famotidine granules by wet granulating famotidine        in the presence of a binder and disintegrant and milling and        screening the product;    -   b) mixing ibuprofen and a glident to produce an        ibuprofen/glident mixture (intermediate mixture I);    -   c) mixing microcrystalline cellulose, silicified        microcrystalline cellulose, low substituted HPC, and        croscarmellose sodium (intermediate mixture II);    -   d) combining the famotidine granules with intermediate mixture        II to produce intermediate mixture III;    -   e) combining intermediate mixture I and intermediate mixture III        to produce intermediate mixture IV;    -   f) combining magnesium stearate to intermediate IV, thereby        producing a ibuprofen/famotidine solid formulation; and,    -   g) compressing the ibuprofen/famotidine solid formulation to        form tablets.

In one embodiment, the famotidine granules in (a) are prepared bycombining and blending famotidine, microcrystalline cellulose,pregelatinized starch and hydroxypropyl cellulose, adding water as thegranulating liquid, drying the famotidine, and milling and screening theproduct.

In one embodiment, the glident in step (b) is colloidal silicon dioxide.

In one embodiment the invention provides a method of making a tabletcomprising ibuprofen and famotidine by:

-   -   a) preparing famotidine granules by wet granulation of 10 parts        famotidine, 50 parts microcrystalline cellulose, 5 parts        pregelatinized starch and 3 parts hydroxylpropyl cellulose,        using water as the liquid, milling and screening the product;    -   b) mixing 400 parts ibuprofen and 0.4 parts colloidal silicon        dioxide to produce intermediate mixture I;    -   c) mixing 2.2 parts microcrystalline cellulose, 9 parts SMCC 50,        9 parts SMCC90, 8 parts low substituted HPC, and 10.4 parts        croscarmellose sodium to produce intermediate mixture II;    -   d) combining the intermediate mixture I and the famotidine        granules incrementally by combining a first portion of        intermediate mixture I with the famotidine granules and mixing,        adding a second portion of intermediate mixture I and mixing,        adding a third portion of intermediate mixture I and mixing, and        optionally combining additional portions, thereby producing        intermediate mixture III;    -   e) combining intermediate mixture II and intermediate mixture        III to produce intermediate mixture IV;    -   f) adding 13 parts magnesium stearate to intermediate IV,        thereby producing a ibuprofen/famotidine solid formulation; and,    -   g) compressing the ibuprofen/famotidine solid formulation to        form tablets.

Using the methods described herein the solid pharmaceutical compositionsof the invention can be formed into tablets with content uniformity(n=10) as shown below.

Mean (% Claim) RSD Ibuprofen 102.3 2.6% Famotidine 101.4 1.9%

Dissolution results indicated at least 95% of ibuprofen or famotidinereleased after 10 minutes (measured under neutral dissolutionconditions).

11.0 Packaging

In one aspect the invention provides a container, such as a vial,containing ibuprofen/famotidine unit dose forms of the invention,instructions to take the medication 3× daily are affixed to thecontainer, or packaged with the container. In one embodiment thecontainer contains a one-month supply of tablets (or other oral dosageform). In one embodiment, for example, the number of tablets in thecontainer is from 89-94 tablets (e.g., 89, 90, 91, 92, 93 or 94tablets). In one embodiment the number of tablets in the container isabout 100 (e.g. 100±10). In a related aspect the invention provides acontainer containing a two-month supply of ibuprofen/famotidine tabletsof the invention. The number of tablets in the container may be about200 (e.g., 200±10) or may be in the range 178-188 tablets.

In a related aspect, the invention provides a container as describedabove, including instructions to take the medication 3× daily, exceptcontaining unit dose forms comprising famotidine and a non-ibuprofenNSAID as described herein (with a number of tablets as described above).In a related aspect, the invention provides a container as describedabove, including instructions to take the medication 3× daily, exceptcontaining unit dose forms comprising famotidine without any NSAID asdescribed herein (with a number of tablets as described above).

12.0 TID Administration of Famotidine

Famotidine may be used for treatment (short term and maintenance) ofduodenal ulcer, short term treatment of active benign gastric ulcer,gastroesophageal reflux disease (GERD), short term treatment ofesophagitis due to GERD and has been administered to treat dyspepsia. Atpresent famotidine is usually administered to BID or QD at a daily doseof 10, 20 or 40 mg. However, as demonstrated in Example 1, TIDadministration of famotidine provides better gastric protection than BIDadministration.

Thus, in an aspect, the invention provides a method for treatment of afamotidine-responsive condition by administering famotidine three timesper day.

In one aspect, the invention provides a method for administeringfamotidine three times per day to treat or prevent NSAID-induceddyspepsia. While generally regarded as safe, a common side effect ofNSAID administration is the development of upper gastrointestinal (GI)symptoms, such as dyspepsia. Among patients taking NSAIDs regularlydyspepsia is reported weekly in up to about 30% of patients and up toabout 15% daily (see, e.g., Larkai et al., 1989, J. Clin. Gastroenterol.11:158-62; Singh et al., 1996, Arch. Intern. Med. 156:1530-6). Thus, inone aspect, the invention provides a method of reducing symptoms ofdyspepsia in a subject in need of NSAID treatment who has experiencedsymptoms of dyspepsia associated with NSAID administration, comprisingadministering to the subject an effective amount of a NSAID incombination with an effective amount of famotidine, wherein thefamotidine is administered three times per day. The two drugs can beadministered concurrently as separate formulations or combined as asingle dosage form. In one embodiment the NSAID is ibuprofen. In variousembodiments the subject requires treatment with the NSAID for at leastone week, at least two weeks, at least one month, or at least threemonths.

13.0 Famotidine Unit Dose Forms Suitable for TID Administration

In an aspect of the invention, a unit dose form comprising famotidineand excipients is provided, where famotidine is the solepharmaceutically active agent and the unit dose form contains famotidinesufficient to deliver a total daily dose of about 80 mg whenadministered on a TID schedule. In one version, for example, thequantity of famotidine is about 26.6 mg (e.g., in the range 24 mg to 28mg) which allows administration of about 80 mg/day with TIDadministration of one tablet, or the quantity of famotidine is about 13mg (e.g., in the range 12 mg to 14 mg, e.g., 13.3 mg) which allowsadministration of 80 mg/day with TID administration of two tablets.Other ranges and amounts are those described hereinabove foribuprofen-famotidine unit dose forms.

In one embodiment famotidine is the only pharmaceutically active agentin the unit dose forms. In one embodiment the unit dose form does notcontain an NSAID.

14.0 Famotidine-NSAID Dose Forms

In an aspect of the invention a unit dose form comprising famotidine,excipients and an NSAID is provided, where the famotidine content issufficient to deliver a total daily dose of 70-85 mg, preferably 75-80mg famotidine when administered three-times per day. Suitable NSAIDsinclude, without limitation, aspirin, diclofenac, meclofenamate,mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin,phenylbutazone, piroxicam, sulindac, tenoxicam, diflunisail, tiaprofenicacid, tolmetin, etodolac, fenoprofen, floctafenine, flurbiprofen,indomethacin, and ketoprofen, as well as ibuprofen. In one embodiment,the NSAID and famotidine are in separate compartments of the unit dose,rather than admixed. In one embodiment, the NSAID is formulated formodified- or sustained release (e.g., so that the NSAID is released overa period of about 8 hours).

15.0 Method of Treatment

In another aspect, the invention provides a method of treating a patientin need of ibuprofen treatment, comprising prescribing or administeringthe ibuprofen/famotidine unit dose forms (e.g., tablets) of theinvention. In one embodiment the patient is instructed to ingest thedrug tablets three times daily. In one embodiment the patient isinstructed to ensure there is at least a 6-hr interval betweenadministrations of consecutive doses.

In one aspect the invention provides a method of treating a patient inneed of ibuprofen treatment, where the patient is at elevated risk fordeveloping an NSAID-induced ulcer. In one aspect the invention providesa method of treating a patient in need of ibuprofen treatment, where thepatient is at high risk for developing an NSAID-induced ulcer.

In one aspect the invention provides a method of reducing, in a subjectin need of ibuprofen treatment, the risk of developing anibuprofen-induced symptom or condition such as ulcer or GERD. Thismethod involves administering to the subject an effective amount of aibuprofen in combination with an effective amount of famotidine, whereinthe famotidine is administered three times per day. In an embodiment,the ibuprofen and famotidine are administered as a single unit dosageform.

In one aspect the invention provides a method of reducing symptoms of afamotidine-responsive condition, such as dyspepsia, in a subject in needof NSAID treatment who has experienced symptoms of afamotidine-responsive condition, such as dyspepsia, associated withNSAID administration, by administering to the subject an effectiveamount of a NSAID in combination with an effective amount of famotidine,wherein the famotidine is administered three times per day. In anembodiment, the ibuprofen and famotidine are administered as a singleunit dosage form.

In one aspect the invention provides a method of reducing symptoms ofdyspepsia in a subject not taking an NSAID, by administering to thesubject an effective amount of famotidine, wherein the famotidine isadministered three times per day.

In a related aspect, the invention provides the use of famotidine incombination with ibuprofen for the manufacture of a medicament fortreatment of an ibuprofen responsive condition, wherein said medicamentis adapted for oral administration in a unit dosage form foradministration three times per day. In a preferred embodiment, the unitdosage form has an amount of famotidine such that TID administrationdelivers about 80 mg famotidine per day (e.g., about 13 mg or about 26.6mg per unit dose form). In a related aspect, the medicament has the formas described herein.

17.0 Business Methods

Also provided is a business method comprising manufacturing, marketing,using, distributing, selling, or licensing, the ibuprofen-famotidineoral dosage forms of the invention. For example, the invention providesa method of doing business comprising (i) manufacturingibuprofen/famotidine tablets of the invention, or having said tabletsmanufactured, and (ii) selling the ibuprofen/famotidine tablets topharmacies or hospitals.

Also provided is a business method comprising manufacturing, marketing,using, distributing, selling, or licensing, the famotidine-only oraldosage forms of the invention. For example, the invention provides amethod of doing business comprising (i) manufacturing famotidine tabletsof the invention, or having said tablets manufactured, and (ii) sellingthe famotidine tablets to pharmacies or hospitals.

The invention also provides a method of doing business by advertising orselling a solid oral unit dosage form of the invention with instructionsto take the dosage form on a TID schedule. In one embodiment the oraldosage form contains famotidine. In one embodiment the oral dosage formcontains famotidine and ibuprofen.

The invention also provides a method of doing business by advertising orselling a solid oral unit dosage form of the invention with instructionsto take the dosage form on a TID schedule.

18.0 Examples 18.1 Example 1 Administration of Famotidine TID ProvidesSuperior Gastric Protection Compared to Administration of Famotidine BID

Pharmocokinetic modeling shows that TID administration of famotidine andibuprofen according to the method of the present invention providesprotection superior to that achieved by conventional cotherapy. FIG. 1Ashows the predicted effect on intragastric pH of administration of 26.6mg famotidine TID. FIG. 1B shows the predicted effect on intragastric pHof administration of 40 mg famotidine BID. Modeling shows that over atwenty-four hour interval, intragastric pH is greater than 3.5 duringfor several more hours per day than achieved using TID administration offamotidine compared to conventional BID dosing. In FIG. 1,administration of 80 mg/day famotidine using TID dosing is shown tomaintain pH greater than 3.5 for about 21 hours per twenty-four hourinterval, while the same daily dose administered BID dosing maintains pHgreater than 3.5 for about 17 hours per twenty-four hour interval. Theprecise duration of pH elevation can be confirmed in clinical trials andmay deviate somewhat from the predicted values (with the TID dosingremaining more effective than the BID dosing).

Methodology: Mean plasma concentration versus time data from a singledose bio equivalence study (world wide web at fda.gov/cder/foi/anda/2001/75-311_Famotidine_Bioeqr.pdf, n=30) comparing 40 mg Pepcid andgeneric famotidine (Teva Pharm) were best fitted to a one compartmentoral absorption model with a lag time using a nonlinear least-squaresregression program, WinNonlin (Pharsight®). The followingpharmacokinetic parameters for Pepcid were obtained:

Parameter Units Estimate V/F L 241.8 k_(a) h⁻¹ 0.8133 k_(el) h⁻¹ 0.2643T_(lag) h 0.3677where V/F is the apparent volume of distribution, k_(a) is theabsorption rate constant, k_(el) is the elimination rate constant andT_(lag) is the absorption lag time.

The relationship between plasma concentrations of Pepcid andintragastric pH in one patient were digitized from FIG. 4 of Echizen andIshizaki, supra, page 189. The digitized plasma concentration vs.intragastric pH were fitted using a nonlinear least-squares regressionprogram, WinNonlin to a sigmoid Emax model using the following equation:

$E = {E_{0} + \frac{E_{\max}*C^{\gamma}}{E\; C_{50}^{\gamma}*C^{\gamma}}}$

where E is the intragastric pH at C, E_(o) is the intragastric pH attime zero, E_(max) is the maximum intragastric pH, EC₅₀ is the Pepcidconcentration at one-half of Emax, C is the plasma concentration ofPepcid and γ is the shape factor. The estimated pharmacodynamicparameters are listed below:

Parameter Units Estimate E_(max) — 7.80 EC₅₀ ng/mL 32.6 E₀ — 1.88 γ —4.80

Using the pharmacokinetic parameters obtained above together with thepharmacodynamic parameters above, plasma concentrations as well asintragastric pH as a function of time were simulated for various doseregimens.

18.2 Example 2 Administration of Famotidine TID Provides SuperiorGastric Protection Compared to Administration of Famotidine BID

A randomized, open-label, two-period, crossover study was carried out tocompare the effects on gastric pH of administration of 80 mg per day offamotidine when administered for five consecutive days in two versusthree divided doses each day.

A. Study Subjects

Thirteen healthy subjects participated in the study. The subjects'demographic parameters are provided in Tables 1 and 2.

TABLE 1 Baseline Demographic Information 9 Male 4 Female Mean Age: 27.2years Range 19-42 Mean Body Mass Index*: 22.8 Range 19-27 *Body massindex (BMI) is calculated as weight (kg)/[height (m)]²

The normal range for BMI varies, however, 20-25 can be considered thenormal range. Nine subjects had a BMI in the normal range (“NormalWeight group”), and four subjects (ID#107, 111, 112 and 113) had a BMIoutside of the normal range (Table 2).

TABLE 2 Baseline Demographic Information Subject # Age Gender Body MassIndex 102 22 Female 21 103 39 Male 22 104 27 Female 23 105 22 Female 22106 23 Male 25 107 26 Male 19 108 42 Male 24 109 26 Male 23 110 29 Male27 111 28 Female 19 112 19 Male 26 113 24 Male 22 201 27 Male 24

B. Study Protocol

Subjects were assigned randomly, in approximately a 1:1 ratio, to one oftwo, two-period treatment sequences as follows:

-   -   Treatment Sequence 1: 40 mg famotidine BID×5 days, followed by        26.6 mg famotidine TID×5 days.    -   Treatment Sequence 2: 26.6 mg famotidine TID×5 days, followed by        40 mg famotidine BID×5 days.

There was a washout of at least one week between administration of thelast dose of Treatment Period 1 and administration of the first dose ofTreatment Period 2.

PEPCID® (famotidine) for Oral Suspension (Merck & Co., Inc., 40 mg/5 mL)was administered with water. During treatment periods in whichfamotidine was administered TID, medication was administered atapproximately 0800, 1600, and 2400 on each day of dosing. Duringtreatment periods in which famotidine is to be administered BID,medication is administered at approximately 0800 and 2000 on each day ofdosing.

All doses of study medication were administered orally, on an open-labelbasis. Subjects were prohibited from taking any medications orinterventions that decrease gastric acid secretion or neutralize gastricacid, and any medications that are known or suspected to cause dyspepsiaor gastrointestinal ulcers, throughout the study period.

Subjects were screened within 20 days prior to study entry and remainedat the study center beginning at approximately 1500 h on Study Day 0 andcontinuing until approximately 1000 h on Study Day 6 of both treatmentperiods. (The first day of dosing for each treatment period isdesignated Study Day 1, and the last day of dosing is designated StudyDay 2). Subjects were followed for 14 days after administration of theirlast dose of study medication.

Gastric pH was measured continuously, using a nasogastric pH probe,during the 24 hours following administration of the first dose of studymedication on Study Day 1, and during the 24 hours followingadministration of the first dose of study medication on Study Day 5,during both treatment periods. Blood samples were collected prior toinitiation of dosing, and prior to administration of the second dose ofstudy medication on Study Day 1 and Study Day 5 during both treatmentperiods for determination of trough plasma famotidine concentrations.For each patient the median pH during a 24 hour period (or subperiodthereof) was calculated. To measure the effect of treatments for a groupof individuals, the average or mean of the measured medians for severalindividuals was determined (i.e., average={[M₁+M₂ . . . M_(x)]/X} where“x” is the number of individuals in the group and each “M” is the medianfor an individual in the group).

C. Results

Based on pH measurements made during the 24 hours followingadministration of the first dose of study medication on Study Day 1during both treatment periods, TID dosing resulted in a higher gastricpH and less time of exposure to acidic conditions than BID dosing(measured as an average of measurements for all subjects or for subjectsof normal weight). This result is consistent with the modeling inExample 1 showing that TID dosing provides better gastric protection. Inaddition, it was discovered that, surprisingly, there was significantlyless patient-to-patient variation in response to treatment under the TIDdosing regimen compared to the BID regimen.

i) Median Gastric pH

The median gastric pH over 24 hours (starting with the firstadministration of study drug) was measured. Table 3 shows the mean of 24hour pH values for all subjects and compares the BID dosing regimen tothe TID dosing regimen. The mean of the 24 hour value (medians) for allsubjects for the BID dosing was 3.3 pH units compared to 3.6 units forthe TID dosing. The 0.3 pH unit difference represents a 300% differencein activity of hydrogen ions.

TABLE 3 24 Hour pH Values BID TID Number 13 13 Mean 3.3 3.6 SD 1.1 0.7Avr. Dev. 0.9 0.6 Range 1.8-5.1 2.5-4.4 Max-Min 3.3 1.9

For the subset of subjects with a BMI in the normal range (“normalweight subjects”) the difference between BID and TID was morepronounced, with a mean pH of 3.1 during the BID period and 3.6 duringthe TID period (Table 4). The 0.5 pH unit difference represents a 500%difference in activity of hydrogen ions.

TABLE 4 24 Hour pH Values for Normal Weight Subjects BID TID Number 9 9Mean 3.1 3.6 SD 1.1 0.7 Avr. Dev 0.9 0.5 Range 1.8-4.0 2.5-4.4 Max-Min2.2 1.9

During the 24 hour pH measurement periods, pH values were recordedduring a variety of conditions such as sitting upright, lying asleep,during meals and just after a meal. Each of these conditions affects thegastric pH in different manner. Specifically, measurements taken whileupright tend to be more consistent due to the position of the pH probewhile values taken during meals are altered due to the acidity of thefood.

Table 5 presents the pH values taken while the subjects were in theupright position, the most reliable measure of gastric pH. As shown, thegastric pH during this period was 0.5 units higher for the TID dosingperiod compared to the BID dosing period. For the subset of normalweight subjects, the difference in pH during the upright period was 0.8units (Table 6) with the TID dosing period having a higher mean pH thanthe BID dosing period.

TABLE 5 pH Values Taken in the Upright Position BID TID Number 13 13Mean 3.2 3.7 SD 1.2 0.8 Avr. Dev. 1.0 0.7 Range 1.8-5.1 2.3-4.7 Max-Min3.3 2.4

TABLE 6 Upright pH Values for the Normal Weight Subjects BID TID Mean3.0 3.8 SD 1.0 0.9 Avr. Dev. 0.8 0.6 Range 1.8-4.6 2.3-4.7 Max-Min 2.82.4

Summary

Mean gastric pH was higher during the first 24 hours of drug dosingduring the TID arm than during the BID arm of the study.

TABLE 7 Amount By Which TID Dosing Provided Superior Gastric ProtectionCompared To BID Dosing (Mean of Group; Expressed as pH Units) Parametermeasured All Subjects Normal Weight Group Gastric pH (24 h) 0.3 0.5Upright Gastric pH 0.5 0.8

TABLE 8 Famotidine Effect on Gastric pH by Subject and Period SubjectDrug type Median pH Median pH No. Period given (24 hour) (Upright) 102 1TID 26.6 mg 3.8 3.8 2 BID 40 mg 4.0 4.0 103 1 BID 40 mg 2.6 2.6 2 TID26.6 mg 2.9 2.9 104 1 TID 26.6 mg 3.6 3.6 2 BID 40 mg 4.8 4.8 105 1 TID26.6 mg 2.5 2.5 2 BID 40 mg 2.0 2.0 106 1 TID 26.6 mg 3.9 3.9 2 BID 40mg 1.8 1.8 107 1 BID 40 mg 4.4 4.4 2 TID 26.6 mg 3.1 3.1 108 1 BID 40 mg3.8 3.8 2 TID 26.6 mg 4.4 4.4 109 1 TID 26.6 mg 4.0 4.0 2 BID 40 mg 3.63.6 110 1 TID 26.6 mg 2.5 3.0 2 BID 40 mg 2.1 2.1 111 1 BID 40 mg 5.15.1 2 TID 26.6 mg 4.5 4.5 112 1 BID 40 mg 4.2 4.2 2 TID 26.6 mg 3.1 3.1113 1 TID 26.6 mg 4.4 4.4 2 BID 40 mg 3.8 3.8 201 1 BID 40 mg 3.6 3.6 2TID 26.6 mg 4.5 4.5

ii) Exposure to Gastric pH Below 3.5

Another important measure of benefit is the duration of time a subjectspends during the 24 hour period with a gastric pH below certaincritical values. The time spent below these values represents timeduring which the subject is at risk for complications such as gastriculcers caused by gastric acid. The pH values that have been examined forthis analysis are pH <3.5 (this section) and pH <4.0 (Section iii,below).

Tables 9-11 show the effect of dosing on the time gastric pH is below3.5. Gastric pH was below 3.5 for 19.5 minutes less (on average) duringthe TID period compared to the BID dosing period (Table 9). For normalweight subjects gastric pH was below 3.5 for 89.3 minutes less duringthe TID period compared to the BID dosing period (Table 10).

TABLE 9 Time Below pH 3.5 BID TID Number 13 13 Average 713.0 693.5 SD211.7 152.2 Avr. Dev. 169.1 124.7 Range 459-1165 514-950 Max-Min 706 436

TABLE 10 Time Below pH 3.5 (Normal Weight Subjects) BID TID Average752.0 662.7 SD 217.8 155.6 Avr. Dev. 175.1 116.7 Range 486-1165 514-950Max-Min 679 436

TABLE 11 Total and Fraction Time pH < 3.5, by Subject and Period SubjectDrug type Time pH < 3.5 Fraction time No. Period given (min) pH < 3.5(%) 102 1 TID 26.6 mg 681 47.3 2 BID 40 mg 654 45.4 103 1 BID 40 mg 91463.5 2 TID 26.6 mg 845 58.7 104 1 TID 26.6 mg 700 48.7 2 BID 40 mg 48633.8 105 1 TID 26.6 mg 950 66 2 BID 40 mg 1165 80.9 106 1 TID 26.6 mg654 45.4 2 BID 40 mg 965 67 107 1 BID 40 mg 560 38.9 2 TID 26.6 mg 78954.8 108 1 BID 40 mg 565 39.2 2 TID 26.6 mg 463 32.1 109 1 TID 26.6 mg578 40.1 2 BID 40 mg 687 47.7 110 1 TID 26.6 mg 904 62.9 2 BID 40 mg 90763 111 1 BID 40 mg 459 31.9 2 TID 26.6 mg 575 40 112 1 BID 40 mg 57539.9 2 TID 26.6 mg 784 54.4 113 1 TID 26.6 mg 514 35.7 2 BID 40 mg 62843.6 201 1 BID 40 mg 704 49.3 2 TID 26.6 mg 579 40.2

iii) Exposure to Gastric pH Below 4.0

Tables 12-14 show the effect of dosing on the time gastric pH is below4.0. Gastric pH was below 4.0 for 23.1 minutes less (on average) duringthe TID period compared to the BID dosing period (Table 12). Forsubjects in the normal weight group gastric pH was below 4.0 for 89.9minutes less during the TID period compared to the BID dosing period(Table 13).

TABLE 12 Time Below pH 4.0 TIME (Minutes) pH < 4 BID TID Number 13 13Average 806.5 783.4 SD 204.0 138.4 Avr. Dev. 158.8 111.9 Range 514-1224589-1048 Max-Min 710 459

TABLE 13 Time Below pH 4.0 (Normal Weight Subjects) TIME (Minutes) pH <4 BID TID Average 854.1 764.2 SD 202.1 145.2 Avr. Dev. 155.7 105.4 Range714-1224 589-1048 Max-Min 510 459

TABLE 14 Total and Fraction Time pH < 4.0, by Subject and Period Time pH< 4 Fraction time Subject No. Period Famotidine (min) pH < 4 (%) 102 1TID 26.6 mg 767 53.2 2 BID 40 mg 714 49.6 103 1 BID 40 mg 1034 71.8 2TID 26.6 mg 934 64.9 104 1 TID 26.6 mg 782 54.3 2 BID 40 mg 547 38.0 1051 TID 26.6 mg 1048 72.8 2 BID 40 mg 1224 85.0 106 1 TID 26.6 mg 737 51.22 BID 40 mg 1005 69.8 107 1 BID 40 mg 640 44.4 2 TID 26.6 mg 855 59.4108 1 BID 40 mg 841 58.4 2 TID 26.6 mg 589 40.9 109 1 TID 26.6 mg 71850.0 2 BID 40 mg 803 55.8 110 1 TID 26.6 mg 962 66.0 2 BID 40 mg 96166.7 111 1 BID 40 mg 514 35.7 2 TID 26.6 mg 644 44.7 112 1 BID 40 mg 68347.4 2 TID 26.6 mg 857 59.5 113 1 TID 26.6 mg 658 45.7 2 BID 40 mg 76353.0 201 1 BID 40 mg 756 52.5 2 TID 26.6 mg 645 44.8

TABLE 15 Summary Mean reduction in time with gastric pH below criticalvalue in subjects receiving drug TID compared to subjects receivng drugBID Parameter measured All Subjects Normal Weight Group time < pH 3.519.5 min 89.3 min time < pH 4.0 23.1 min 89.9 min

iv) Less Patient-to-Patient Variability

The data provided above demonstrate that when famotidine wasadministered TID, less subject-to-subject variation in gastric pH wasobserved than when famotidine was administered BID. As shown in Table 16(compiled from Tables 3-15) the subject-to-subject variability isconsiderably less for TID dosing compared to BID dosing, as measured bystandard deviation, average absolute deviation and range. For example,the range of 24 hour pH values for BID dosing was 1.8 to 5.1, or 3.3 pHunits, between the minimum value and the maximum value. By comparison,the range was 2.5 to 4.4, or a 1.9 pH units, for TID dosing.

Decreased variability has important clinical implications. Byextrapolation from these data, when famotidine (or famotidine andibuprofen) is administered to a large population of patients, fewerpatients will experience gastric pH levels markedly different from thegroup average. Thus, any individual patient treated withibuprofen/famotidine according to the present invention is less likelyto experience the detrimental effects of low gastric pH that would bethe case with BID dosing of famotidine. That is, the incidence of sideeffects in a population treated according to the present invention canbe expected to be lower than in an equivalent population receiving BIDdosing.

TABLE 16 Reduced Subject-to-Subject Variability BID TID pH Range(max-min) 3.3 pH units 1.9 pH units Average Absolute Deviation 0.9 0.5Standard Deviation 1.1 0.7 pH Range (max-min), normal weight subjects2.2 pH units 1.9 pH units Average Absolute Deviation 0.9 0.5 StandardDeviation 1.1 0.7 pH Range (max-min) in upright position 3.3 pH units2.4 pH units Average Absolute Deviation 1.0 0.7 Standard Deviation 1.20.8 pH Range (max-min) in Upright position, normal weight subjects 2.8pH units 2.4 pH units Average Absolute Deviation 1.0 0.9 StandardDeviation 0.8 0.6 Time below pH 3.5 range (min-max) 706 min 436 minAverage Absolute Deviation 169.1 124.7 Standard Deviation 211.7 152.2Time below pH 3.5 range (min-max), normal weight subjects 679 min 436min Average Absolute Deviation 175.1 116.7 Standard Deviation 217.8155.6 Time below pH 4.0 range (min-max) 710 min 459 min Average AbsoluteDeviation 158.8 111.9 Standard Deviation 204.0 138.4 Time below pH 4.0range (min-max), normal weight subjects 510 min 459 min Average AbsoluteDeviation 155.7 105.4 Standard Deviation 202.1 145.2

v) Patient 106

As discussed above, for most of the subjects studied, TID dosingprovided an increase in gastric protection, and this protection wasaccompanied by less patient-to-patient variability in response. Notably,the 24-hour median gastric pH was below 2.5 for three patients in theBID period, but for no patients in the TID period.

Response in individual patients varied, as is expected foradministration of any drug regimen. The data in Table 17 illustrate thatvery significant differences in gastric protection may be seen in somepatients.

TABLE 17 Subject 106 Summary Parameter BID period TID period DifferenceMedian pH 1.8 3.9 2.1 pH Units Median pH (Upright) 1.8 4.0 2.2 pH UnitsTime pH < 4 1005 min 737 min 268 min (% of 24-hour period) (69.8%)(51.2%)

vi) Summary

It will be appreciated from this disclosure (see Examples 1-3) thatadministration of famotadine and ibuprofen according to the presentinvention results in one or more advantages over conventionaladministration:

1. Superior gastric protection when administered to a population ofindividuals (i.e., patients in need of ibuprofen treatment or famotidinetreatment) especially populations of normal weight individuals.

2. Reduced interpatient variability when administered to a population ofindividuals resulting in a reduction in side-effects and improvedsafety.

3. High magnitude individual benefit in a subset of patients for whomgastric pH is substantially elevated using the methods of the inventionwhen compared to BID dosing.

18.3 Example 3 Pharmacokinetic Drug-Drug Interaction Study of Ibuprofenand Famotidine in Healthy Male Subjects

This example demonstrates that pharmocokinetic parameters of concurrentadministration of ibuprofen and famotidine (as in the unit dose forms ofthe invention) are bioequivalent to separate administration of the twoAPIs. An open-label, randomized, single-dose, oral administration,two-period crossover study was conducted. Six male subjects wereassigned randomly to Sequence 1 or Sequence 2:

Sequence 1

-   -   Period 1: 800 mg ibuprofen [Motrin®], followed 24 hr later by 40        mg famotidine [Pepcid®].    -   Period 2: Concurrent administration of 800 mg ibuprofen and 40        mg famotidine.

Sequence 2

-   -   Period 1: Concurrent administration of 800 mg ibuprofen and 40        mg famotidine.    -   Period 2: 800 mg of ibuprofen, followed 24 hr later by 40 mg        famotidine.

Following administration of ibuprofen and famotidine plasma ibuprofenand/or famotidine concentrations were determined in samples collectedpredose and at 0.25, 0.5, 1.0, 1.5, 2, 4, 6, 8, 10, 12, 14, 18, and 24hr after administration of ibuprofen and/or famotidine. Ibuprofen andfamotidine plasma concentrations, and computed pharmacokineticparameters, were listed and summarized by dose (mean, standarddeviation, 95% confidence interval, minimum, maximum). Individual andmean (by time) concentration-versus-time curves for each treatment,plotted on a semi-log scale, were examined. Intra-subject comparisonswere made between Period 1 and Period 2.

WinNonLin version 2.1 was used to analyze the pharmacokinetic parametersfrom the concentration-versus-time data based a non-compartmental model.The pharmacokinetic values then were transferred to MS Excel or GraphpadPrism for calculation of means, SDs, confidence intervals, etc., forpreparation of tables and figures, and for performance of statisticaltesting.

Analyses of variance appropriate for a two-period crossover design wereperformed on the computed parameters including terms for sequence,subject within sequence, formulation, and period. Analyses wereperformed on the observed data and on natural logarithm-transformed datafor area under the concentration-versus-time curve (AUC) and maximumobserved plasma concentration (C_(max)). Ninety-five (95) % confidenceintervals were computed for the differences in treatment means.

After confirming the absence of a period effect for the pharmacokineticparameters, individual AUC and C_(max) data were pooled for eachtreatment (i.e., for both ibuprofen and famotidine administered aloneand in combination) for bioequivalence testing. The individual data thenwere log-transformed (natural log) and the differences for each drugbetween administration alone versus in combination were determined foreach subject. The means and 95% confidence intervals of theselog-transformed differences were calculated, and the upper and lowerbound of the log-transformed range were normalized and then tested forbioequivalence. These intervals were evaluated in relation to thecriterion equivalence interval of 80% to 125% for log-transformed data.Tables 18-20 show the results of the analyses:

TABLE 18 Pharmacokinetic Parameters (mean ± SD, 95% CI) for Ibuprofenand Famotidine When Administered Alone and In Combination IbuprofenFamotidine Parameter Alone With Famotidine Alone With Ibuprofen t_(max)(hr) (95% CI) 1.58 ± 0.49 2.25 ± 1.89 1.67 ± 0.52 2.17 ± 0.93(1.07-2.10) (0.27-4.23) (1.13-2.21) (1.19-3.14) C_(max) (ng/mL) 56,279 ±8,486  55,666 ± 12,106 143 ± 31  159 ± 50  (95% CI) (47,374-65,184)(42,961-68,370) (111-175) (107-211) t_(1/2) (hr) (95% CI) 2.50 ± 0.552.56 ± 0.59 3.66 ± 0.19 3.49 ± 0.35 (1.92-3.07) (1.95-3.18) (3.46-3.86)(3.12-3.85) K_(el) (95% CI) 0.29 ± 0.06 0.28 ± 0.06 0.19 ± 0.01 0.20 ±0.02 (0.23-0.35) (0.22-0.34) (0.18-0.20) (0.18-0.22) AUC_((last))236,992 ± 62,862  234,851 ± 67,655  883 ± 173 934 ± 275 (ng/mL · hr)(95% CI) (171,023-302,961) (163,851-305,850)  (701-1064)  (646-1222) AUC245,124 ± 63,697  235,156 ± 67,749  893 ± 175 944 ± 279 (ng/mL · hr)(95% CI) (178,279-311,970) (164,058-306,254)  (710-1077)  (651-1236)

TABLE 19 Bioequivalence Test Results for AUC (log-transformed values)for Ibuprofen and Famotidine When Administered Alone Versus InCombination AUC(_(last)) AUC_((last)) In Drug Alone CombinationDifference 95% CI Ibuprofen 12.35 12.33 0.02 0.94-1.11 Famotidine 6.7656.799 −0.034 0.79-1.19 ¹ Test criterion: CI within 0.8-1.25

TABLE 20 Bioequivalence Test Results for C_(max) (log-transformedvalues) for Ibuprofen and Famotidine When Administered Alone Versus InCombination C_(max) C_(max) In Drug Alone Combination Difference 95% CIIbuprofen 10.93 10.91 0.02 0.85-1.23 Famotidine 4.94 5.02 −0.080.76-1.12 ¹Test criterion: CI within 0.8-1.25

There were no significant differences between the treatment means forthe pharmacokinetic parameters for either ibuprofen or famotidine whenadministered alone versus in combination. It was concluded that bothibuprofen and famotidine can be considered bioequivalent whenadministered in combination compared to separate administration.

18.4 Example 4 Trough Concentrations of Famotidine

Trough concentrations of famotidine were determined in blood samplesfrom the subjects of the study described in Example 2. Samples werecollected prior to initiation of dosing, and prior to administration ofthe second dose of study medication on Study Day 1 and Study Day 5during both treatment periods. The results are presented in Table 21below.

TABLE 21 Trough Plasma Concentration of Famotidine Plasma Concentrationof Famotidine (ng/mL) 40 mg BID 26.6 mg TID Day 1 Day 5 Day 1 Day 5 Mean10.5 15.7 9.7 15.7 SD 2.8 4.6 4.9 8.9

If more frequent dosing of famotidine led to plasma accumulation, theday 5 trough data for TID dosing would be significantly higher than thetrough values for day 5 with BID dosing. As can be seen, the troughplasma values for the two dosing regimen were the same (15.7 ng/mL). Itcan be concluded from this that TID dosing does not lead to plasmaaccumulation of famotidine.

18.5 Example 5 Ibuprofen-Famotidine Compatibility Studies

As shown in Table 22, substantial degradation of famotidine was observedin the famotidine-ibuprofen mixture (1:29 ratio) under stress conditionsin the presence of ibuprofen. In the absence of ibuprofen, famotidine isstable.

TABLE 22 Famotidine/Ibuprofen Stability Under Stress ConditionsFamotidine API Storage condition Content* Famotidine 2 weeks at 60° C.98% Famotidine + Ibuprofen 2 weeks at 60° C. 81% Famotidine + Ibuprofen1 mo at 40° C./75% RH 54% *Famotidine content was determined byanalytical HPLC and expressed as percent of target content.

Similarly, as shown in Table 23 substantial degradation of famotidinewas observed in the tablet dosage form containing ibuprofen in a tabletformulation under stress conditions. The tablets contained 10 mgfamotidine, 800 mg ibuprofen and the following excipients:pregelatinized starch (Starch 1500); hydroxypropyl cellulose; colloidalsilicon dioxide; microcrystalline cellulose (Emcocel® 50M and 90M); SMCC(ProSolv® 50); SMCC (ProSolv® 90); low substituted HPC (LH-11);croscarmellose; sodium; and magnesium stearate. The tablets wereprepared as described in Example 8-5 of U.S. Patent App. Pub. No.2007-0043096 A1, which is incorporated by reference.

TABLE 23 Stability of Famotidine in Tablet Under Stress ConditionsStorage Famotidine Drugs in Tablet Formulation Condition Content*Famotidine (13.3 mg) + Ibuprofen (400 mg) Initial 100% Famotidine (13.3mg) + Ibuprofen (400 mg) 1 week at 60° C.  39% Famotidine (13.3 mg) +Ibuprofen (400 mg) 1 month at  83% 40° C./75% RH Famotidine (13.3 mg) +Ibuprofen (400 mg) 2 months at  55% 40° C./75% RH Famotidine (13.3 mg) +Ibuprofen (400 mg) 3 months at  32% 40° C./75% RH *Famotidine contentwas determined by analytical HPLC and expressed as percent of targetcontent.

TABLE 24A Stability of Famotidine in Tablet (400 mg Ibuprofen, 10 mgFamotidine) Under Stress Conditions Amt. of Stage Conditions IbuprofenAmt. of famotidine 1 month at 25° C./60% RH 100.3 98.8 8 months atambient temp. 101.4 97.3 1 week at 60° C. 93.0 60.2 1 month at 60° C.99.1 4.1 “Amt. of ibuprofen/famotidine” refers to the amount of drugremaining at the end of the storage period (as % of original content).Drug content was determined by analytical HPLC.

In other studies, approximately 0.5 g famotidine API was mixed with 14.5g ibuprofen. After grinding, API mixture was stored in glass vials underthe conditions indicated. As shown in Table 24B, substantial degradationof famotidine was observed.

TABLE 24B Famotidine/Ibuprofen Stability Under Stress Conditions APIIbuprofen (% control) Famotidine (% control) Mixture 1 wk 40° C. 1 wk60° C. 2 wks 60° C. 1 wk 40° C. 1 wk 60° C. 2 wks 60° C. Famotidine 96.1121.0 100.1 Famotidine-Ibuprofen 104.7 99.9 96.4 94.4 85.7 46.0

18.6 Example 6 Determination of Dissolution

One method for determination of the rate and extent of dissolution canbe carried out using the methods described in the United StatesPharmacopeia and National Formulary 29th Revision, under the followingconditions:

-   -   Dissolution Apparatus: Apparatus II (Paddles)    -   Dissolution Medium: 50.0 mM Potassium Phosphate Buffer, pH 7.2    -   Dissolution Medium Volume: 900 mL    -   Temperature in Vessel: 37.0° C.±0.5° C.    -   Speed: 50 RPM    -   Sampling Time: 10 min 20 min., 30 min., 45 min 60 min and        infinity @ 250 rpm for 15 min    -   Sampling Volume: 1 mL    -   Sinker: None

When desired, the dissolution medium or other parameters may be varied.Typically a unit dose form is added to the vessel and dissolution isstarted. At specified times a portion (e.g., 2 ml) of medium iswithdrawn and the amount of API in solution is determined using routineanalytical methods (e.g., HPLC).

The assay above was used to determine the dissolution characteristics ofa unit dose form prepared as described in Example 9 (following storagefor 1 month 25° C./60% RH) with the result shown in Table 25.

TABLE 25 % Released Time (min) Ibuprofen Famotidine 5 43.7 28.9 10 94.977.7 15 97.6 90.0 30 98.4 99.8 45 98.5 102.2 60 98.6 103.1 75 99.2 104.1

18.7 Example 7 Manufacture of Ibuprofen/Famotidine Unit Dose Forms

This example describes how to make a particular ibuprofen/famotidineunit dose form.

A. Producing the Ibuprofen Core

TABLE 26 % mg/ Item Material w/w tablet Function/Supplier 1. IbuprofenUSP 64.00 800 API/BASF 2. Lactose Monohydrate NF 24.00 300 Binder/Kerry(80M) Biosci. 3. Colloidal Silicon Dioxide NF 0.48 6 Glidant/Cabot(Cab-O-Sil M5P) 4. Croscarmellose Sodium NF 2.40 30 Disintegrant/FMCAc-di-Sol  5A. Hypromellose USP, Methocel 1.44 18 Binder/Dow E-5 LVPremium (Intragranular in dry mix)  5B Hypromellose USP, Methocel 0.48 6Binder/Dow E-5 LV Premium (Intragranular as solution) 6. Purified WaterUSP — q.s. 7. Prosolv SMCC 90 (silicified 3.76 47 Binder/JRSmicrocrystalline cellulose) 8. Croscarmellose Sodium NF 2.40 30Disintegrant/FMC (Ac-di-Sol) 9. Colloidal Silicon Dioxide NF 0.32 4.0Glidant/Cabot (Cab-O-Sil M5P) 10. Magnesium Stearate NF 0.72 9.0Lubricant/Peter Greven Core tablet weight 100.0 1250

Items 1-5A are sifted through Quadro Comil 16-mesh and mixed (Blend 1).Item 5B is dissolved in water and slowly added to Blend 1 using a mixer.Additional water is added and mixed. The wet material is dried at 50° C.for 12 h, milled using a 16-mesh screen with appropriate spacer, anddried until the LOD at 50° C. is below 0.5% w/w. Dried granules andextra granular material is transferred to a 3 cu. ft. V blender and mixfor 3 minutes.

Items 7-9 are sifted through Quadro Comil using 16-mesh screen withappropriate spacer.

Item 10 (lubricant) is sifted through 30 mesh hand screen andtransferred to the above blender and mixed for 3 minutes. The finalblend is compressed into tablets using a DC 16 compression machine setwith 0.3750×0.8125 caplet shaped punches. The target tablet weight is1250 mg with range of 3.0% and hardness of 10-20 Kp.

B. Barrier Layer

The compressed tablets are coated with Opadry II white (Y-22-7719)according to manufacturer's instructions to a weight gain of 1.5-2.0%w/w.

C. Famotidine layer

Famotidine and Opadry II (Colorcon) are mixed at a 1:1 ratio and theunit dose form amount of famotidine is applied by spray coating.

D. Over Coating Layer

Opadry II white is applied over the famotidine layer by spray coating.

18.8 Example 8 Manufacture of Ibuprofen/Famotidine Unit Dose Forms

In one version, the oral dosage form comprises many small particles offamotidine coated with a barrier layer and situated in a matrixcontaining ibuprofen.

A famotidine suspension (75% famotidine, 20% Opadry, 5% talc) is sprayedonto microcrystalline cellulose (Avicel PH 101) to 100% buildup. Theparticles are coated with a barrier coating comprised of Opadry II White(cat. #Y-22-7719) and then coated with a protective coating comprised ofa PEG 6000 and microcrystalline cellulose (1:1).

The famotidine granules are mixed with ibuprofen granules (prepared asdescribed in Table 27, infra) in a proportion that results in anibuprofen:famotidine (800:26.6) mixture. Colliodal silicon dioxide,croscarmellose, silicified microcrystalline cellulose, and magnesiumstearate are added to the ibuprofen-famotidine mixture, and theresulting mixture is compressed into tablets containing 800 mg ibuprofenand 26.6 mg famotidine (calculated weight).

Optionally the tablets can be coated with a protective coating(overcoating layer).

If ibuprofen DC85 (BASF Aktiengesellschaft, Ludwigshafen, Germany) isused colliodal silicon dioxide, croscarmellose, silicifiedmicrocrystalline cellulose may be omitted.

18.9 Example 9 Manufacture of Ibuprofen/Famotidine Unit Dose Forms

This example describes manufacture of a tablet containing ibuprofengranules and coated famotidine granules.

A. Ibuprofen Granule

TABLE 27 Item Material % w/w mg/tablet Function/Supplier 1. Ibuprofen 25USP 68.96 800 API/BASF 2. Lactose Monohydrate NF (80M) 25.86 300Binder/Kerry Biosci 3. Colloidal Silicon Dioxide NF 0.52 6 Glidant/Cabot(Cab-O-Sil M5P) 4. Croscarmellose Sodium NF Ac-di-Sol 2.59 30Disintegrant/FMC 5A. Hypromellose USP, Methocel E-5 LV 1.55 18Binder/Dow Premium (Intragranular in dry mix) 5B Hypromellose USP,Methocel E-5 LV 0.52 6 Binder/Dow Premium (Intragranular as solution) 6.Purified Water USP — q.s. Process aid Total weight 100.0 1160

Items 1-5A are sifted through Quadro Comil 16-mesh and mixed (Blend 1).Item 5B is dissolved in water and slowly added to Blend 1 using a mixer.Additional water is added and mixed. The wet material is dried at 50° C.for 12 h, milled using a 16-mesh screen with appropriate spacer, anddried until the LOD at 50° C. is below 0.5% w/w. Dried granules andextra granular material is transferred to a V-blender and mixed for 3minutes.

B. Famotidine Granule

TABLE 28 % mg/ Item Material w/w tablet Function/Supplier STEP-I (SprayGranulation-Top Spray) 1 Microcrystalline Cellulose 45.47 35.5 Inertmaterial/FMC NF (Avicel PH 101) 2 Famotidine USP 34.05 26.6 Active/DRL 3Opadry II white (Y-22-7719) 9.09 7.1 Coating/Colorcon 4 Talc NF 2.30 1.8Glidant/Imperial 5 Purified water USP N/A q.s. Process aid STEP-II(Barrier Coating-Bottom Spray) 1 Opadry White (YS-1-7003) 9.09 7.1Coating/Colorcon 2 Purified water USP N/A q.s. Process aid Total weight100.0 78.1

Set up the Glatt fluid bed processor and add microcrystalline celluloseto Glatt. Disperse famotidine in purified water under mechanicalstirring for 5 minutes. Add Opadry followed by talc and let it run for30 minutes. Homogenize the above suspension for 20-30 minutes. Keepmixing at slow speed to avoid air entrapment

Set up the peristaltic pump and spray the drug suspension completely.Dry the product to a product temperature of around 40-44°. Sift thespray granulated famotidine through Quadro comil #20 mesh.

Spray Opadry suspension equivalent to 10% weight gain in the Glatt fluidbed processor. Dry the final product to a product temperature of around40-44° C. Discharge and sift it through ASTM #30 mesh to remove anyagglomerate.

C. Final Blending

TABLE 29 Item Material % w/w mg/tablet Function/Supplier 1 IbuprofenGranules 87.34 1160.0 Process Granule 2 Famotidine Coated 5.88 78.10Process Granule Granules 3 Prosolv SMCC 90 3.54 47.00 Diluent/JRS 4Croscarmellose 2.26 30.00 Disintegrant/FMC Sodium NF 5 Colloidal Silicon0.30 4.00 Glidant/Cabot Dioxide NF 6 Magnesium 0.68 9.00 Lubricant/PeterGreven Stearate NF Total weight 100.0 1328.1

Weigh appropriate amount of ibuprofen granules, famotidine granules andthe extra-granular materials. Blend geometrically famotidine andibuprofen granules in appropriate blenders.

Add the sifted extra-granular materials (Prosolv SMCC 90, croscarmellosesodium and colloidal silicon dioxide sifted through 16-mesh screen) toabove granules and mix for 3 minutes.

Sift magnesium stearate through 30 mesh screen and transfer to the aboveblender and lubricate for 3 minutes.

D. Tabletting

Set DC-16 compression machine with bisect punches and compress the blendto tablets with target weight of 1.328 g, hardness of 10-20 Kp,disintegration time less than 15 minutes.

E. Film Coating

TABLE 30 % mg/ Item Material w/w tablet Function/Supplier 1Ibuprofen/famotidine Granules 1328.1 Process Granule/PII 2 Opadry IIWhite (85F18422) ~3.0 39.90 Coating/Colorcon 3 Purified water USP q.s.Process aid/PII Total weight 100.0 1368.0

Disperse Opadry II white (85 F18422) in water under mechanical stirring.Continue mixing for 45 minutes at slow speed. Load approximately 80-90kg of compressed tablets in Acella Cota with a 48″ coating pan. Coat thetablets to a weight gain of 2.5-3.5% w/w following optimum coatingparameters.

In other related embodiments tablets are made as above except that theamount of any non-API component can vary from the amounts above by up toplus or minus 10%. For example, the lactose monohydrate component inTable 27 could vary in the range from about 23.3 to about 28.4. APIs canvary in amounts as described elsewhere herein.

18.10 Example 10 Stability of Ibuprofen/Famotidine Tablet (800/26.6 mg)with Opadry Coatings

As described above, a barrier layer separating ibuprofen and famotidinecan be comprised of a wide variety of compounds. Many suitable coatingmaterial are commercially available as “Opadry” including, for exampleOpadry II White (Colorcon Code Y-22-7719) which contains HPMC, Glycerol,Polydextrose, Titanium Dioxide, Triacetate, and Macrogol; Opadry white(Colorcon Code YS-1-7003) HPMC 2910, PEG 400, Polysorbate 80, andTitanium Dioxide; and Opadry II White (Colorcon Code 85F18422) whichcontains PVA-partial hydrolyzed, Titanium Dioxide (E171), Macrogol 3350,and Talc.

Tablets were prepared essentially as described in Example 9 (“OpadryWhite YS-1-7003”) or essentially as described in Example 8 (i.e., as inExample 9 except that Opadry II [Y-22-7719] was used instead of OpadryWhite in the barrier layer and an additional protective layer wasapplied by coating with a suspension of PEG 6000 and microcrystallinecellulose [1:1] in water). As shown in Table 31, use of Opadry White inthe barrier layer gave superior results compared to Opadry II White.

TABLE 31 EFFECT OF BARRIER COAT ON FAMOTIDINE STABILITY (TOTALFAMOTIDINE IMPURITIES) Opadry II (Y-22-7719) Opadry White (YS-1-7003)Time Impurities % Impurities % Initial 0.5 0.5 1 wk 50° C. 51.0 2.0 2 wk40° C./75% RH 3.6 0.4 1 mo 40° C./75% RH 6.5 0.5 ***

All publications and patent documents (patents, published patentapplications, and unpublished patent applications) cited herein areincorporated herein by reference as if each such publication or documentwas specifically and individually indicated to be incorporated herein byreference. Citation of publications and patent documents is not intendedas an admission that any such document is pertinent prior art, nor doesit constitute any admission as to the contents or date of the same. Theinvention having now been described by way of written description andexample, those of skill in the art will recognize that the invention canbe practiced in a variety of embodiments and that the foregoingdescription and examples are for purposes of illustration and notlimitation of the following claims.

1. A method for treating a patient with an ibuprofen-responsivecondition comprising: administering to said patient a first dose of anoral dosage form comprising from 775 mg to 825 mg ibuprofen and from 25mg to 28 mg famotidine, the ibuprofen and famotidine being present in aweight ratio in the range 29:1 to 31:1, wherein the ibuprofen and thefamotidine are formulated for immediate release; administering to saidpatient a second dose of the oral dosage form; administering to saidpatient a third dose of the oral dosage form, wherein the first dose,the second dose, and the third dose are administered within a 24 hourdosing cycle, wherein the ibuprofen and the famotidine are in separatecompartments in the oral dosage form, and wherein the patient does notsuffer at the times of administering from a condition characterized byhypersecretion of gastric acid and/or from active severe oesophagitisand/or Barrett's ulceration, and/or from gastroesophageal refluxdisease. 2.-5. (canceled)
 6. An oral dosage form comprising from 775 mgto 825 mg ibuprofen and from 25 mg to 28 mg famotidine, the ibuprofenand famotidine being present in a weight ratio in the range 29:1 to31:1, wherein the ibuprofen and the famotidine are formulated forimmediate release and wherein the ibuprofen and the famotidine are inseparate compartments in the oral dosage form.
 7. The oral dosage formof claim 6 comprising a first portion containing ibuprofen and a secondportion containing famotidine, wherein the famotidine is in the form ofbarrier-coated particles distributed in the ibuprofen portion. 8.(canceled)
 9. (canceled)
 10. The method of claim 1 wherein the oral unitdosage form comprises about 800 mg ibuprofen and about 26.67 mgfamotidine and the total daily dose is about 2400 mg ibuprofen and about80 mg famotidine.
 11. (canceled)
 12. The oral dosage form of claim 6wherein the oral unit dosage form comprises about 800 mg ibuprofen andabout 26.6 mg famotidine and the total daily dose is about 2400 mgibuprofen and about 80 mg famotidine.
 13. A method for manufacturing anoral dosage form of claim 6 wherein the method comprises the steps of:providing granules comprising ibuprofen, at least one binder, at leastone disintegrant, and at least one glidant; blending the granules withat least one binder, at least one disintegrant, at least one glidant,and at least one lubricant; compressing the blend to form a core;optionally coating the core with a barrier coat; applying a layercomprising famotidine to said core; and optionally applying anovercoating layer to yield the oral dosage form.
 14. The method of claim13 wherein the oral dosage form has a content uniformity of at leastabout 95%.
 15. The method of claim 13 wherein the oral dosage form has acontent uniformity of at least about 97%.
 16. A container comprising aplurality of oral dosage forms of claim 6 and instructions to take theoral dosage form three times daily to treat an ibuprofen-responsivecondition, wherein the instructions are affixed to the container orpackaged with the container.
 17. A method comprising: manufacturing aplurality of oral dosage forms of claim 6, and selling the oral dosageform to pharmacies or hospitals with instructions to take the oraldosage form three times daily to treat an ibuprofen-responsivecondition.